Section 2 Neuropathology

*Glia in Health and Disease*

2013;**12**(1):64-82

in human astrocytes: A paradox for neuronal protection. Journal of Neurochemistry. 2003;**78**(4):842-853

[81] Vécsei L, Szalárdy L, Fülöp F, Toldi J. Kynurenines in the CNS: Recent advances and new questions. Nature Reviews Drug Discovery.

[82] Xu Z, Zeng W, Sun J, Chen W, Zhang R, Yang Z, et al. The

quantification of blood-brain barrier disruption using dynamic contrastenhanced magnetic resonance

imaging in aging rhesus monkeys with spontaneous type 2 diabetes mellitus. NeuroImage. 2017;**158**:480-487

[83] Penninx BWJH. Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms. Neuroscience and Biobehavioral Reviews. 2017;**74**:277-286

[84] Unger JW, Livingston JN, Moss AM.

signalling mechanisms and functional aspects. Progress in Neurobiology.

[85] Yahfoufi N, Alsadi N, Jambi M, Matar C. The Immunomodulatory and anti-inflammatory role of polyphenols.

[86] Cho J-H, Johnson GVW. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules. Journal of Neurochemistry. 2010;**88**(2):349-358

Nutrients. 2018;**10**(11):1618

Insulin receptors in the central nervous system: Localization,

1991;**36**(5):343-362

**78**

**81**

**Chapter 5**

**Abstract**

parts of the brain.

**1. Introduction**

inflammation [4].

inflammation, oxidative stress

*and Adrián Jordá*

Astrocytes and Inflammatory

*Soraya L. Valles, Federico Burguet, Antonio Iradi,* 

*Martin Aldasoro, Jose M. Vila, Constanza Aldasoro* 

Processes in Alzheimer's Disease

A significant increase in inflammation has been shown to be a crucial factor in the progression of the Alzheimer's disease (AD). Moreover, inflammatory signals are already present in mild cognitive impairment (MCI) patients before they develop AD. The amyloid hypothesis argues that in AD, there is an increase in oxidative stress caused by the accumulation of β-amyloid (Aβ) and that its elimination should be a priority. Also, hyperphosphorylation of the protein TAU occurs, which is characteristic of this disease. In AD oxidative stress processes occur and also inflammation. The basal chronic inflammation produces a cascade of cellular, such as astrocytes and microglial cells, and molecular processes in AD patients. We here have tried to explore the action of the inflammatory process and its implication in the neurodegenerative process of the AD. We can see that the role of Aβ is only one component that gives rise to inflammation, probably mediated by activation of microglia and astrocytes with the goal of getting rid of these brain waste products. In fact, it is related to a greater degree with the progression of the disease and worsening of the symptoms with the increase of phosphorylated TAU in different

**Keywords:** astrocytes, microglia, neuroprotection, Alzheimer's disease,

Inflammation is a physiological process in response to various factors such as infection, trauma, and a long list of diseases that can promote it [1]. It is not uncommon to think that changes or failures that occur in their action mechanisms can lead to fatal consequences for humans. The inflammation originates because of a set of immune cells involved in the process that causes different changes in the inflamed area through signaling pathways composed of different groups of pro and antiinflammatory molecules [2]. The resolution of the inflammatory process happens after the neutralization of the trigger. The cells of the immune system generate an anti-inflammatory activity, including lipoxins (for example, LXA4, RvE1) and cytokines such as interleukin-10 and interleukin-37, transforming growth factorbeta (IL-10, IL-37, TGF-β) [3]. Acute inflammatory processes will be resolved relatively quickly, while, however, resolution processes are not achieved in chronic

### **Chapter 5**

## Astrocytes and Inflammatory Processes in Alzheimer's Disease

*Soraya L. Valles, Federico Burguet, Antonio Iradi, Martin Aldasoro, Jose M. Vila, Constanza Aldasoro and Adrián Jordá*

### **Abstract**

A significant increase in inflammation has been shown to be a crucial factor in the progression of the Alzheimer's disease (AD). Moreover, inflammatory signals are already present in mild cognitive impairment (MCI) patients before they develop AD. The amyloid hypothesis argues that in AD, there is an increase in oxidative stress caused by the accumulation of β-amyloid (Aβ) and that its elimination should be a priority. Also, hyperphosphorylation of the protein TAU occurs, which is characteristic of this disease. In AD oxidative stress processes occur and also inflammation. The basal chronic inflammation produces a cascade of cellular, such as astrocytes and microglial cells, and molecular processes in AD patients. We here have tried to explore the action of the inflammatory process and its implication in the neurodegenerative process of the AD. We can see that the role of Aβ is only one component that gives rise to inflammation, probably mediated by activation of microglia and astrocytes with the goal of getting rid of these brain waste products. In fact, it is related to a greater degree with the progression of the disease and worsening of the symptoms with the increase of phosphorylated TAU in different parts of the brain.

**Keywords:** astrocytes, microglia, neuroprotection, Alzheimer's disease, inflammation, oxidative stress

### **1. Introduction**

Inflammation is a physiological process in response to various factors such as infection, trauma, and a long list of diseases that can promote it [1]. It is not uncommon to think that changes or failures that occur in their action mechanisms can lead to fatal consequences for humans. The inflammation originates because of a set of immune cells involved in the process that causes different changes in the inflamed area through signaling pathways composed of different groups of pro and antiinflammatory molecules [2]. The resolution of the inflammatory process happens after the neutralization of the trigger. The cells of the immune system generate an anti-inflammatory activity, including lipoxins (for example, LXA4, RvE1) and cytokines such as interleukin-10 and interleukin-37, transforming growth factorbeta (IL-10, IL-37, TGF-β) [3]. Acute inflammatory processes will be resolved relatively quickly, while, however, resolution processes are not achieved in chronic inflammation [4].

The differences between both types of inflammation, acute and chronic, reside at different levels. Regarding the cells involved in acute inflammation, neutrophils intervene in an infection context and eosinophils and mast cells in the case of allergies [5]. The chemical mediators involved in acute inflammation would be the complementary system, the kinins, the prostaglandins, the leukotrienes, the cytokines coming from several immune cells, and the gamma interferon of the T lymphocytes [6]. The lesions that are produced in this type of inflammation are itching, pus, and abscesses [7]. On the other hand, in chronic inflammation, we would have the participation of macrophages and lymphocytes mainly, which would produce cytokines as the main chemical mediators of this type of inflammation. As alterations, we would also have a rash (in the context of a cutaneous disease), and unlike the findings we had in the acute, in chronic we can have fibrosis and granuloma. These last two injuries are ultimately responsible for the effects of deterioration at central nervous system (CNS) and peripheral (SNP) level [8]. The study of neurodegenerative diseases excluded inflammation as an etiological agent of the disease. This was because there were no infiltrates of inflammatory cell similar to those that occur in infectious or autoimmune diseases [9]. Nowadays, there is an increasing amount of studies that position inflammation as being responsible for neurodegeneration through the participation of macrophages and the complementary system [10].

### **2. Specification of the process at the brain level**

In the brain there is no reddening, local heat, or pain after acute inflammation. In the case of chronic inflammation in another organ, the participation of different immune cells takes place. But in the CNS, macrophages are essentially the representatives of the immune system [11].

In the CNS, the derivatives of tissue macrophages would be the microglia of the central nervous system. Microglia participate in numerous maintenance functions such as synapse management, neurogenesis, regulation of certain cognitive processes, and immunological protection [12]. Thus, the main hypothesis on the pathogenesis of Alzheimer's disease (AD) is that the plaques of β-amyloid (Aβ) and neurofibrillary tangles produce an acute inflammation in the brain, which activates these cells causing different inflammatory mediators, such as: proinflammatory cytokines, chemokines, macrophage inflammatory proteins, monocyte chemoattractant proteins, prostaglandins, leukotrienes, thromboxanes, coagulation factors, reactive oxygen species (and other radicals), nitric oxide (NO), complement factors, proteases, protease inhibitors, pentraxins, and C-reactive protein [13]. Due to the chemical composition of the Aβ plaques and neurofibrillary tangles, they stimulate a chronic inflammatory reaction with the intention of eliminating these brain structures [13]. Finally, this inflammatory reaction will produce a neuronal dystrophy mediated by the inflammatory mediators that are secreted by the microglial and astrocyte cells, as well as by the aggregates of amyloid fibrils [14].

### **3. Pathophysiology of Alzheimer's disease**

The pathophysiology of Alzheimer's disease is very varied and there are different hypotheses on how it develops: the most accepted hypothesis in recent years was the amyloid hypothesis. The amyloid precursor protein (APP) will be able to be processed by either α-secretase, β-secretase, or γ-secretase. Depending on which enzyme does the app cut, we can have more or less neuroprotective profile; the α-secretase cleave produced a more neuroprotective one, while on the other hand,

**83**

γ-secretase [22].

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

harmful to neurons, producing greater amount of Aβ [13].

if the β- and γ-secretase participate sequentially, we will obtain metabolites that are

α-Secretases are a family of proteolytic enzymes that adhere to APP in their transmembrane region. The secretases adhere to the fragment that, however, is processed by β-secretases and γ-secretases and that increases the β amyloid peptide [15]. These enzymes are members of the ADAM (disintegrin and metalloprotease domain) family that are expressed on cell surfaces. Furthermore, a metabolite by the action of secretase is APPsα, which has a not only neuroprotective action, but also neurotrophic effects have been observed and, therefore, neuroplasticity can be

The amyloid plaques are composed of a fragment of the APP: the 4-kD amyloid-β protein. The enzymatic processing of APP, resulting in Aβ, requires two enzymes: the γ-secretase, which is dependent on presenilin, and β-secretase, which is an aspartyl protease β-site APP-cleaving enzyme (BACE) (also known as Asp2, memapsin 2) [17, 18]. The BACE1 will function to split the APP, giving as result the βCTF (beta C-terminal fragment), which will later be cleaved again by γ-secretase to give rise to Aβ. On the other hand, this second excision could be caused by a mechanism different from that carried out by γ-secretase, which would be dependent on a 20S proteasome and whose malfunction would lead to an overproduction

There are two BACEs, BACE1 and BACE2. BACE2 is a homolog discovered later than the enzyme BACE1 and shares 64% of similarity in its structure. By contrast, BACE2 is expressed at low levels in neurons and does not have the same activity against APP as BACE1 [20]. The BACE1 is doubly increased in the brains of patients with AD, compared to the brains of individuals without the disease.

For this reason, it is considered that this enzyme is responsible for

the initiation or acceleration of AD. Other studies show how BACE1 is also increased in response to stress: during oxidative stress, hypoxia ischemia, apop-

Research on the proteolytic processing of APP has provided information on the pathogenesis of Alzheimer's disease and on an unusual form of regulation of proteolytic processing within the domains of some membrane proteins, including APP, Notch, and ErbB4 [21]. Some of the enzymes responsible for α and β cleavage are already known. However, the molecular events that are involved in the cleavage produced by the γ-secretase, within the transmembrane domain of these proteins, are much more complex. Presenilins and nicastrin are necessary for this process. While the role of presenilins, in some cases, supports the idea that presenilins are found in the active site of the γ-secretase, other data indicate that they could have a more indirect function, as for example in the transport of substrates to the subcellular compartment for cleavage by the enzyme

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

**3.1 Role of α-secretase**

**3.2 Role of β- and γ-secretases**

of Aβ in the same way [19].

**3.3 The β-secretase: BACE**

tosis, and brain trauma [18].

**3.4 The γ-secretase**

favored [16].

if the β- and γ-secretase participate sequentially, we will obtain metabolites that are harmful to neurons, producing greater amount of Aβ [13].

## **3.1 Role of α-secretase**

*Glia in Health and Disease*

The differences between both types of inflammation, acute and chronic, reside at different levels. Regarding the cells involved in acute inflammation, neutrophils intervene in an infection context and eosinophils and mast cells in the case of allergies [5]. The chemical mediators involved in acute inflammation would be the complementary system, the kinins, the prostaglandins, the leukotrienes, the cytokines coming from several immune cells, and the gamma interferon of the T lymphocytes [6]. The lesions that are produced in this type of inflammation are itching, pus, and abscesses [7]. On the other hand, in chronic inflammation, we would have the participation of macrophages and lymphocytes mainly, which would produce cytokines as the main chemical mediators of this type of inflammation. As alterations, we would also have a rash (in the context of a cutaneous disease), and unlike the findings we had in the acute, in chronic we can have fibrosis and granuloma. These last two injuries are ultimately responsible for the effects of deterioration at central nervous system (CNS) and peripheral (SNP) level [8]. The study of neurodegenerative diseases excluded inflammation as an etiological agent of the disease. This was because there were no infiltrates of inflammatory cell similar to those that occur in infectious or autoimmune diseases [9]. Nowadays, there is an increasing amount of studies that position inflammation as being responsible for neurodegeneration through the participation of macrophages and the complementary system [10].

In the brain there is no reddening, local heat, or pain after acute inflammation. In the case of chronic inflammation in another organ, the participation of different immune cells takes place. But in the CNS, macrophages are essentially the represen-

In the CNS, the derivatives of tissue macrophages would be the microglia of the central nervous system. Microglia participate in numerous maintenance functions such as synapse management, neurogenesis, regulation of certain cognitive processes, and immunological protection [12]. Thus, the main hypothesis on the pathogenesis of Alzheimer's disease (AD) is that the plaques of β-amyloid (Aβ) and neurofibrillary tangles produce an acute inflammation in the brain, which activates these cells causing different inflammatory mediators, such as: proinflammatory cytokines, chemokines, macrophage inflammatory proteins, monocyte chemoattractant proteins, prostaglandins, leukotrienes, thromboxanes, coagulation factors, reactive oxygen species (and other radicals), nitric oxide (NO), complement factors, proteases, protease inhibitors, pentraxins, and C-reactive protein [13]. Due to the chemical composition of the Aβ plaques and neurofibrillary tangles, they stimulate a chronic inflammatory reaction with the intention of eliminating these brain structures [13]. Finally, this inflammatory reaction will produce a neuronal dystrophy mediated by the inflammatory mediators that are secreted by the microg-

lial and astrocyte cells, as well as by the aggregates of amyloid fibrils [14].

The pathophysiology of Alzheimer's disease is very varied and there are different hypotheses on how it develops: the most accepted hypothesis in recent years was the amyloid hypothesis. The amyloid precursor protein (APP) will be able to be processed by either α-secretase, β-secretase, or γ-secretase. Depending on which enzyme does the app cut, we can have more or less neuroprotective profile; the α-secretase cleave produced a more neuroprotective one, while on the other hand,

**3. Pathophysiology of Alzheimer's disease**

**2. Specification of the process at the brain level**

tatives of the immune system [11].

**82**

α-Secretases are a family of proteolytic enzymes that adhere to APP in their transmembrane region. The secretases adhere to the fragment that, however, is processed by β-secretases and γ-secretases and that increases the β amyloid peptide [15]. These enzymes are members of the ADAM (disintegrin and metalloprotease domain) family that are expressed on cell surfaces. Furthermore, a metabolite by the action of secretase is APPsα, which has a not only neuroprotective action, but also neurotrophic effects have been observed and, therefore, neuroplasticity can be favored [16].

### **3.2 Role of β- and γ-secretases**

The amyloid plaques are composed of a fragment of the APP: the 4-kD amyloid-β protein. The enzymatic processing of APP, resulting in Aβ, requires two enzymes: the γ-secretase, which is dependent on presenilin, and β-secretase, which is an aspartyl protease β-site APP-cleaving enzyme (BACE) (also known as Asp2, memapsin 2) [17, 18]. The BACE1 will function to split the APP, giving as result the βCTF (beta C-terminal fragment), which will later be cleaved again by γ-secretase to give rise to Aβ. On the other hand, this second excision could be caused by a mechanism different from that carried out by γ-secretase, which would be dependent on a 20S proteasome and whose malfunction would lead to an overproduction of Aβ in the same way [19].

## **3.3 The β-secretase: BACE**

There are two BACEs, BACE1 and BACE2. BACE2 is a homolog discovered later than the enzyme BACE1 and shares 64% of similarity in its structure. By contrast, BACE2 is expressed at low levels in neurons and does not have the same activity against APP as BACE1 [20]. The BACE1 is doubly increased in the brains of patients with AD, compared to the brains of individuals without the disease. For this reason, it is considered that this enzyme is responsible for the initiation or acceleration of AD. Other studies show how BACE1 is also increased in response to stress: during oxidative stress, hypoxia ischemia, apoptosis, and brain trauma [18].

### **3.4 The γ-secretase**

Research on the proteolytic processing of APP has provided information on the pathogenesis of Alzheimer's disease and on an unusual form of regulation of proteolytic processing within the domains of some membrane proteins, including APP, Notch, and ErbB4 [21]. Some of the enzymes responsible for α and β cleavage are already known. However, the molecular events that are involved in the cleavage produced by the γ-secretase, within the transmembrane domain of these proteins, are much more complex. Presenilins and nicastrin are necessary for this process. While the role of presenilins, in some cases, supports the idea that presenilins are found in the active site of the γ-secretase, other data indicate that they could have a more indirect function, as for example in the transport of substrates to the subcellular compartment for cleavage by the enzyme γ-secretase [22].

### **3.5 Role of β-secretase: BACE1 and γ-secretase in voltage regulation by sodium channel**

The sodium channels Na1s are responsible for regulating for regulating the passage of Na<sup>+</sup> in the initial axonal fragments, Ranvier nodes, and neuromuscular junctions. These channels are formed by an α-subunit in the form of pore and two accessory β subunits which are transmembrane that modify the localization, surface cell expression, and inactivation of the alpha subunit by direct interaction, specially β2 subunit of the Na-1 channel that plays an important role since it undergoes degradation by BACE1 and γ-secretase [23]. These enzymes cleave an intracellular fragment of the C-terminal fraction that results in a transcription factor for Na1.1 mRNA and other protein levels, so that Na 1.1 levels accumulate intracellularly [23]. This fact explains the decreased expression of sodium channels on the surface of the hippocampal neurons of patients with AD, as well as in neuroblastoma cells producing BACE1, resulting in a lower sodium current density [23].

### **3.6 Differences between Aβ40 and Aβ42**

To better understand the fact why Aβ42 promotes, to a greater extent, inflammation in AD than the Aβ40 peptide, it is necessary to emphasize its greater propensity to form amyloid plaques [24]. Studies performed by combining molecular dynamics and nuclear magnetic resonance (NMR) experiments with respect to the behavior of both peptides in water have shown that the Aβ42 peptide forms tangles more prominently [24, 25]. The differences that exist at the level of the chemical formula between the two peptides are only two amino acid residues at the C-terminus. However, at the level of biochemical and conformational interactions, there are clear differences [25]. In addition, while the N-terminal half presents a much smaller spectrum of possible conformations in its secondary structure, the C-terminal half of the Aβ42 peptide allows a greater number of possible conformations. Despite this, these studies showed that Aβ42 is more structured in water than Aβ40 [24]. Specifically, it is appreciated that the Aβ42 form has less flexibility than Aβ40 in its C-terminal half. This fact is produced by the formation of a beta hairpin in the sequence IIGLMVGGVVIA, involving short fragments of the structure between the residues of amino acids 31–34 and 38–41, reducing the flexibility in the Aβ42 peptide. Specifically, this must be the cause of the greater capacity to form amyloid plaques. On the other hand, a β-turn type VIB, centered on residues 35 and 36, is important for the alignment of the threads involved. In addition, the existence of hydrogen bonds between the pairs A30-A42, I32-V40, and L34-G38 adds stability to the structure of the beta fork [24, 25].

### **4. Identification and definition of the problem-question**

In epidemiological studies of Alzheimer's disease, a significant increase in inflammation has been shown to be a crucial factor in the progression of the disease, as well as in the activation of microglia and in the increase of reactive astrocytes in these patients [26]. It should be noted that inflammatory signals are already present in mild cognitive impairment (MCI) patients before they develop AD [27]. In this study, we have tried to explore the action of the inflammatory process associated with Alzheimer's disease and its implication in the neurodegenerative process of the disease.

**85**

classic plaques [42].

*5.1.2 Role of lipopolysaccharide (LPS)*

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

tive stress occurs relatively early in the course of the disease.

**5.1 Mediators of the inflammatory process in AD**

ment or with MCI before they develop AD [27].

the hippocampus compared to adult mice [41].

*5.1.1 Cytokines*

Glial cells have a very important role in the protection of the central nervous system against damage and also in the repair of damaged nerve tissue [28]. Within the glia, astrocytes are the cell type prevalent in the brain [29]. Astrocytes increase neuronal viability and mitochondrial biogenesis, protecting neural cells from oxidative stress and inflammation induced by the toxic amyloid peptide [30–32]. Conversely, if chronic inflammation occurs, astrogliosis is triggered, produced by a reaction to inflammation and oxidative stress caused by toxic and inflammatory agents [33]. In Alzheimer's disease, complex changes and specific conflicts occur in different brain regions. The number of reactive astrocytes increases, engulfing and reducing the amyloid plaques. In addition, astrocytes surround the amyloid plaques and secrete proinflammatory factors, such as tumor necrosis factor (TNF) or interleukin 1 (IL-1) [34]. Currently, no hypothesis about what causes Alzheimer's disease has obtained favorable results. For years, it has been believed that the amyloid theory was the correct one and it was the most supported and financed by almost all the pharmaceutical companies around the world. The amyloid hypothesis argues that in AD, there is an increase in oxidative stress caused by the accumulation of Aβ and that its elimination should be a priority. There is a lot of research showing that increased levels of ROS have been linked to Alzheimer's disease [30, 35] but the effects of antioxidants in clinical studies have been disappointing either because high concentrations of antioxidants are pro-oxidants, or because the oxida-

In AD, different cytokines have been detected, such as IL-1α, IL-1β, IL-6 and, similarly, higher amounts of the type B receptor IL-8 (IL-8RB) have also been found (in neurons in addition to the rest immune cells), unlike the type A receptor for IL-8RA that is only found in immune cells [36, 37]. It was already demonstrated that inflammatory signals are previously present in patients with mild cognitive impair-

The cytokine IL-1β constitutes one of the first secreted cytokines in response to lesions, as it is an important mediator of proliferation, differentiation, and apoptosis [38, 39]. The concentration of the said cytokine has been increased near the sites where the amyloid plaques are located [40]. More recently, it was observed that old mice had an increased basal neuroinflammation and they express IL-1β and IL-10 in

A study conducted in autopsies of 10 patients clinically diagnosed with AD showed that they had amyloid plaques and immunoreactivity for the cytokine IL-6. On the other hand, the control patients did not have immunoreactivity for IL-6 whether they presented plaques or not. From the plaques that were positive for the cytokine IL-6, it could be observed that they were most frequently found in diffuse plaques, less frequently in primitive plaques, and rarely found in compact and

The role of lipopolysaccharides in Alzheimer's disease has been studied by several research groups and it has been observed that treatment with these LPS induces chronic neuroinflammation [43, 44] and can contribute to deficits in learning

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

**5. Interest of the review**

### **5. Interest of the review**

*Glia in Health and Disease*

**channel**

passage of Na<sup>+</sup>

density [23].

**3.6 Differences between Aβ40 and Aβ42**

**3.5 Role of β-secretase: BACE1 and γ-secretase in voltage regulation by sodium** 

The sodium channels Na1s are responsible for regulating for regulating the

To better understand the fact why Aβ42 promotes, to a greater extent, inflam-

mation in AD than the Aβ40 peptide, it is necessary to emphasize its greater propensity to form amyloid plaques [24]. Studies performed by combining molecular dynamics and nuclear magnetic resonance (NMR) experiments with respect to the behavior of both peptides in water have shown that the Aβ42 peptide forms tangles more prominently [24, 25]. The differences that exist at the level of the chemical formula between the two peptides are only two amino acid residues at the C-terminus. However, at the level of biochemical and conformational interactions, there are clear differences [25]. In addition, while the N-terminal half presents a much smaller spectrum of possible conformations in its secondary structure, the C-terminal half of the Aβ42 peptide allows a greater number of possible conformations. Despite this, these studies showed that Aβ42 is more structured in water than Aβ40 [24]. Specifically, it is appreciated that the Aβ42 form has less flexibility than Aβ40 in its C-terminal half. This fact is produced by the formation of a beta hairpin in the sequence IIGLMVGGVVIA, involving short fragments of the structure between the residues of amino acids 31–34 and 38–41, reducing the flexibility in the Aβ42 peptide. Specifically, this must be the cause of the greater capacity to form amyloid plaques. On the other hand, a β-turn type VIB, centered on residues 35 and 36, is important for the alignment of the threads involved. In addition, the existence of hydrogen bonds between the pairs A30-A42, I32-V40, and L34-G38 adds stability to the structure

**4. Identification and definition of the problem-question**

In epidemiological studies of Alzheimer's disease, a significant increase in inflammation has been shown to be a crucial factor in the progression of the disease, as well as in the activation of microglia and in the increase of reactive astrocytes in these patients [26]. It should be noted that inflammatory signals are already present in mild cognitive impairment (MCI) patients before they develop AD [27]. In this study, we have tried to explore the action of the inflammatory process associated with Alzheimer's disease and its implication in the neurodegenerative process

junctions. These channels are formed by an α-subunit in the form of pore and two accessory β subunits which are transmembrane that modify the localization, surface cell expression, and inactivation of the alpha subunit by direct interaction, specially β2 subunit of the Na-1 channel that plays an important role since it undergoes degradation by BACE1 and γ-secretase [23]. These enzymes cleave an intracellular fragment of the C-terminal fraction that results in a transcription factor for Na1.1 mRNA and other protein levels, so that Na 1.1 levels accumulate intracellularly [23]. This fact explains the decreased expression of sodium channels on the surface of the hippocampal neurons of patients with AD, as well as in neuroblastoma cells producing BACE1, resulting in a lower sodium current

in the initial axonal fragments, Ranvier nodes, and neuromuscular

**84**

of the disease.

of the beta fork [24, 25].

Glial cells have a very important role in the protection of the central nervous system against damage and also in the repair of damaged nerve tissue [28]. Within the glia, astrocytes are the cell type prevalent in the brain [29]. Astrocytes increase neuronal viability and mitochondrial biogenesis, protecting neural cells from oxidative stress and inflammation induced by the toxic amyloid peptide [30–32]. Conversely, if chronic inflammation occurs, astrogliosis is triggered, produced by a reaction to inflammation and oxidative stress caused by toxic and inflammatory agents [33]. In Alzheimer's disease, complex changes and specific conflicts occur in different brain regions. The number of reactive astrocytes increases, engulfing and reducing the amyloid plaques. In addition, astrocytes surround the amyloid plaques and secrete proinflammatory factors, such as tumor necrosis factor (TNF) or interleukin 1 (IL-1) [34]. Currently, no hypothesis about what causes Alzheimer's disease has obtained favorable results. For years, it has been believed that the amyloid theory was the correct one and it was the most supported and financed by almost all the pharmaceutical companies around the world. The amyloid hypothesis argues that in AD, there is an increase in oxidative stress caused by the accumulation of Aβ and that its elimination should be a priority. There is a lot of research showing that increased levels of ROS have been linked to Alzheimer's disease [30, 35] but the effects of antioxidants in clinical studies have been disappointing either because high concentrations of antioxidants are pro-oxidants, or because the oxidative stress occurs relatively early in the course of the disease.

### **5.1 Mediators of the inflammatory process in AD**

### *5.1.1 Cytokines*

In AD, different cytokines have been detected, such as IL-1α, IL-1β, IL-6 and, similarly, higher amounts of the type B receptor IL-8 (IL-8RB) have also been found (in neurons in addition to the rest immune cells), unlike the type A receptor for IL-8RA that is only found in immune cells [36, 37]. It was already demonstrated that inflammatory signals are previously present in patients with mild cognitive impairment or with MCI before they develop AD [27].

The cytokine IL-1β constitutes one of the first secreted cytokines in response to lesions, as it is an important mediator of proliferation, differentiation, and apoptosis [38, 39]. The concentration of the said cytokine has been increased near the sites where the amyloid plaques are located [40]. More recently, it was observed that old mice had an increased basal neuroinflammation and they express IL-1β and IL-10 in the hippocampus compared to adult mice [41].

A study conducted in autopsies of 10 patients clinically diagnosed with AD showed that they had amyloid plaques and immunoreactivity for the cytokine IL-6. On the other hand, the control patients did not have immunoreactivity for IL-6 whether they presented plaques or not. From the plaques that were positive for the cytokine IL-6, it could be observed that they were most frequently found in diffuse plaques, less frequently in primitive plaques, and rarely found in compact and classic plaques [42].

### *5.1.2 Role of lipopolysaccharide (LPS)*

The role of lipopolysaccharides in Alzheimer's disease has been studied by several research groups and it has been observed that treatment with these LPS induces chronic neuroinflammation [43, 44] and can contribute to deficits in learning

and memory [44–46]. As previously known, LPS is an activator of microglia in the central nervous system and can induce a 2-fold increase in the expression of APP in the brains of mice with the Swedish mutation for APP [47]. In addition, it also caused an 18-fold increase in βCTF, suggesting an increased activity in turn of BACE1 and in turn an increase by up to three times in the amount of Aβ40 and Aβ42 [47]. While the previous study observed an increase in the brain in a non-specific manner, another study specifically analyzed the increase in glial fibrillary acidic protein (GFAP) positive astrocytes in the cortex and hippocampus after treatment with LPS [48].

### **5.2 Alzheimer's disease as taupathy**

### *5.2.1 Structure of the TAU protein*

In electrophoresis gels, the TAU protein has been found in different isoforms depending on how the RNA has been processed and different levels of phosphorylation. This RNA is located on chromosome 17, it has at least 16 exons [49]. Other proteins besides tubulin have been described that can bind to the TAU protein: spectrin protein phosphatase 1, protein phosphatase 2a, presenilin 1, α-synuclein. Recent studies that have used mass spectrophotometry techniques indicate that it is more appropriate to measure the bacterially expressed MT-binding region (MTBR) domain of TAU, instead of the total TAU protein, this technic is more accurate to calculate the amount of TAU neurofibrillary tangles [50].

### *5.2.2 AD as taupathy*

The TAU protein is a member of the microtubule-associated proteins (MAPs). The microtubules in the cells have a multitude of functions, among which we can highlight at the level of the neurons the formation of dendrites, axons, and their specific contacts [51]. Therefore, the TAU protein is necessary for the functioning and development of the nervous system and the presence of modified forms of the TAU protein gives rise to important pathological effects in the neurons that leads to neurodegeneration. Specifically in AD, phosphorylation of TAU protein is produced by glycogen synthase 3ß (GSK3) [49]. This TAU protein is abnormally phosphorylated and will form the neurofibrillary tangles in the neuronal cytoplasm, constituting one of the most important histological features of Alzheimer's disease. As previous works demonstrated, the number of these balls will be directly related to the severity of the symptoms of the disease [52]. The structure of these microtubules will be formed by double helix subunits that are intertwined with levorotatory filaments that are composed of the following proteins: intermediate filaments, neurofilaments of medium and high molecular weight; proteins associated with microtubules MAP2 and TAU; actin; and ubiquitins [53, 54], which show characteristics different from normal neurofilaments and normal microtubules.

In 1995, a study in autopsies done with eight patients with diagnostic criteria for Alzheimer's disease and six control patients of similar ages indicated important changes between TAU and inflammation. The brain of these 15 subjects was extracted without exceeding 15 h of postmortem and, later, samples were taken from the hippocampus; from the frontal, temporal, and occipital lobes; and from the cerebellum. AD patients presented a direct relationship between higher concentrations of the activated IL-α and higher load of neuritic plaque TAU2+ (TAU 2-immunoreactive). There is a strong association between the presence of IL-1α +, microglia, and TAU protein plates in patients with Alzheimer's disease [55]. Recently, it was observed in a microglial culture model together with neurons that the inflammatory response mediated by LPS-induced microglia leads to

**87**

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

hyperphosphorylation of TAU mediating the greater kinase of the TAU protein, GSK3β (kinase glycogen synthase kinase 3β) [56]. On the other hand, chronic inflammation causes phosphorylation of TAU and worsens pathology in neurons that express many inflammatory receptors and molecules, including, MHC-I, TNFR1, IL-1R, and TLR. As a result of this, it allows them to interact directly with microglia [57]. Inflammatory signals can consequently directly activate neuronal protein kinases and phosphatases, such as cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3β (GSK3β), ERK, and protein-phosphatase 2A (PP2A), which regulates phosphorylation of TAU and the assembly of neuronal microtu-

TAU, and its function regarding neuronal and microglial interactions in brain immune chain reactions, as in AD and its progression, could be initiated, by agerelated chronic inflammation. There is an increase in scientific evidence suggesting the importance of the mechanism in the synaptic pruning regulation, neurogenesis, immunological chain reaction-mediated cognitive functions in brain cells, and LTP,

The mechanisms of inflammation effects on TAU and its pathological influx remain constant even if broad investigations have been carried out on Aβ and inflammation pathway. Persistent microglial activity and inflammation are established to be the causes of a broad release of TAU sub-species [44–47]. As for the mechanisms of TAU-induced inflammatory responses leading to pathology, several sources point to an acceleration of the onset of main protein kinases, which take care of the phosphorylation of the TAU protein. Microglia-perpetuated liberation of TNF-α has proven to provoke the accumulation and aggregation of TAU in in vitro neurons [48]. On the other hand, blocking microglia with minocycline reduces the inflammatory response and propagation of pathology related to TAU in experiments performed with hTau mouse models [60]. Moreover, the inhibition of inflammation by arginase-1 overexpression counteracts the activity of nitric oxide synthases, and facilitates autophagy and the decrease of TAU pathology in the TAU-transgenic mouse model rTg4510 [61]. A process that has been reported as important in stressinduced mechanisms and which can be genetically suppressed by the corticotropinreleasing factor receptor is the stimulation of toll-like receptor 4 (TLR4), which

To perform the "synaptic pruning" by the microglia, a cytosine secreted by the neural cells called fraktalkine (CX3CL1) that is excreted in large quantities in the brain compared to the rest of the organs of the body is needed [63]. Its receptor CX3CR1 is expressed in large quantities by microglia [64]. Previously, it was demonstrated that neuroinflammation via the receptor deficiency for fractalkine (CX3CR1) promotes taupathy and neurodegeneration in mouse models in which systemic inflammation mediated by LPS had occurred. First, Mapt+/+ neurons

even if its complete relevance is still to be confirmed [44].

increases GSK-3β and CDK-5, which phosphorylate TAU [62].

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

bules [43, 44, 58, 59] (**Figure 1**).

*TAU protein in health and Alzheimer's disease.*

**Figure 1.**

*Astrocytes and Inflammatory Processes in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.88701*

**Figure 1.** *TAU protein in health and Alzheimer's disease.*

*Glia in Health and Disease*

**5.2 Alzheimer's disease as taupathy**

calculate the amount of TAU neurofibrillary tangles [50].

*5.2.1 Structure of the TAU protein*

*5.2.2 AD as taupathy*

and memory [44–46]. As previously known, LPS is an activator of microglia in the central nervous system and can induce a 2-fold increase in the expression of APP in the brains of mice with the Swedish mutation for APP [47]. In addition, it also caused an 18-fold increase in βCTF, suggesting an increased activity in turn of BACE1 and in turn an increase by up to three times in the amount of Aβ40 and Aβ42 [47]. While the previous study observed an increase in the brain in a non-specific manner, another study specifically analyzed the increase in glial fibrillary acidic protein (GFAP) positive astrocytes in the cortex and hippocampus after treatment with LPS [48].

In electrophoresis gels, the TAU protein has been found in different isoforms depending on how the RNA has been processed and different levels of phosphorylation. This RNA is located on chromosome 17, it has at least 16 exons [49]. Other proteins besides tubulin have been described that can bind to the TAU protein: spectrin protein phosphatase 1, protein phosphatase 2a, presenilin 1, α-synuclein. Recent studies that have used mass spectrophotometry techniques indicate that it is more appropriate to measure the bacterially expressed MT-binding region (MTBR) domain of TAU, instead of the total TAU protein, this technic is more accurate to

The TAU protein is a member of the microtubule-associated proteins (MAPs). The microtubules in the cells have a multitude of functions, among which we can highlight at the level of the neurons the formation of dendrites, axons, and their specific contacts [51]. Therefore, the TAU protein is necessary for the functioning and development of the nervous system and the presence of modified forms of the TAU protein gives rise to important pathological effects in the neurons that leads to neurodegeneration. Specifically in AD, phosphorylation of TAU protein is produced by glycogen synthase 3ß (GSK3) [49]. This TAU protein is abnormally phosphorylated and will form the neurofibrillary tangles in the neuronal cytoplasm, constituting one of the most important histological features of Alzheimer's disease. As previous works demonstrated, the number of these balls will be directly related to the severity of the symptoms of the disease [52]. The structure of these microtubules will be formed by double helix subunits that are intertwined with levorotatory filaments that are composed of the following proteins: intermediate filaments, neurofilaments of medium and high molecular weight; proteins associated with microtubules MAP2 and TAU; actin; and ubiquitins [53, 54], which show characteristics different from normal neurofilaments and normal microtubules. In 1995, a study in autopsies done with eight patients with diagnostic criteria for Alzheimer's disease and six control patients of similar ages indicated important changes between TAU and inflammation. The brain of these 15 subjects was extracted without exceeding 15 h of postmortem and, later, samples were taken from the hippocampus; from the frontal, temporal, and occipital lobes; and from the cerebellum. AD patients presented a direct relationship between higher concentrations of the activated IL-α and higher load of neuritic plaque TAU2+ (TAU 2-immunoreactive). There is a strong association between the presence of IL-1α +, microglia, and TAU protein plates in patients with Alzheimer's disease [55]. Recently, it was observed in a microglial culture model together with neurons that the inflammatory response mediated by LPS-induced microglia leads to

**86**

hyperphosphorylation of TAU mediating the greater kinase of the TAU protein, GSK3β (kinase glycogen synthase kinase 3β) [56]. On the other hand, chronic inflammation causes phosphorylation of TAU and worsens pathology in neurons that express many inflammatory receptors and molecules, including, MHC-I, TNFR1, IL-1R, and TLR. As a result of this, it allows them to interact directly with microglia [57]. Inflammatory signals can consequently directly activate neuronal protein kinases and phosphatases, such as cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3β (GSK3β), ERK, and protein-phosphatase 2A (PP2A), which regulates phosphorylation of TAU and the assembly of neuronal microtubules [43, 44, 58, 59] (**Figure 1**).

TAU, and its function regarding neuronal and microglial interactions in brain immune chain reactions, as in AD and its progression, could be initiated, by agerelated chronic inflammation. There is an increase in scientific evidence suggesting the importance of the mechanism in the synaptic pruning regulation, neurogenesis, immunological chain reaction-mediated cognitive functions in brain cells, and LTP, even if its complete relevance is still to be confirmed [44].

The mechanisms of inflammation effects on TAU and its pathological influx remain constant even if broad investigations have been carried out on Aβ and inflammation pathway. Persistent microglial activity and inflammation are established to be the causes of a broad release of TAU sub-species [44–47]. As for the mechanisms of TAU-induced inflammatory responses leading to pathology, several sources point to an acceleration of the onset of main protein kinases, which take care of the phosphorylation of the TAU protein. Microglia-perpetuated liberation of TNF-α has proven to provoke the accumulation and aggregation of TAU in in vitro neurons [48]. On the other hand, blocking microglia with minocycline reduces the inflammatory response and propagation of pathology related to TAU in experiments performed with hTau mouse models [60]. Moreover, the inhibition of inflammation by arginase-1 overexpression counteracts the activity of nitric oxide synthases, and facilitates autophagy and the decrease of TAU pathology in the TAU-transgenic mouse model rTg4510 [61]. A process that has been reported as important in stressinduced mechanisms and which can be genetically suppressed by the corticotropinreleasing factor receptor is the stimulation of toll-like receptor 4 (TLR4), which increases GSK-3β and CDK-5, which phosphorylate TAU [62].

To perform the "synaptic pruning" by the microglia, a cytosine secreted by the neural cells called fraktalkine (CX3CL1) that is excreted in large quantities in the brain compared to the rest of the organs of the body is needed [63]. Its receptor CX3CR1 is expressed in large quantities by microglia [64]. Previously, it was demonstrated that neuroinflammation via the receptor deficiency for fractalkine (CX3CR1) promotes taupathy and neurodegeneration in mouse models in which systemic inflammation mediated by LPS had occurred. First, Mapt+/+ neurons

showed high levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when they were grown together with microglia Cx3cr1<sup>−</sup>/<sup>−</sup> treated with LPS. Second, a population of positive neurons for TAU protein phospho-S199 (AT8) in the dentate gyrus is also positive for (CC3) for mice treated with Cx3cr1<sup>−</sup>/<sup>−</sup>. Third, the genetic deficiency of TAU in Cx3cr1<sup>−</sup>/<sup>−</sup> mice resulted in reduced microglial activation, which altered the expression of inflammatory genes in those neurons positive for CC3 compared to Cx3cr1<sup>−</sup>/<sup>−</sup> mice [44]. These results suggest that pathological changes in TAU mediate the neurotoxicity induced by inflammation, while Mapt deficiency is neuroprotective. It was proposed that this earlier phenomenon was probably associated with the indirect reduction of microglial activity due to the decrease in the production of pathological species of TAU, observed in a transgenic mouse model rTg4510, which expresses the mutation in P310L (4R0N TauP301L) and initiates taupathy within 3–5 months. Brain stimulation of TLR4 by LPS in the aforementioned mouse model also produces activation of microglia and phosphorylation of TAU [65]. In another investigation using the 3xTg-AD transgenic mouse model, which develops both Aβ and taupathies, chronic treatment with LPS results in phosphorylation of CDK5-dependent TAU without affecting Aβ levels in adult animals (~6 months old). TAU phosphorylation was observed by immunohistochemistry techniques when treated with LPS and PBS samples of the aforementioned 3xTg-AD mice by two tests: in the first one in the Ser202/Thr205 residues that were recognized by AT8, they presented up to twice as much AT8 activity in the samples treated with LPS as those that were administered PBS; the second test detected that in the Thr231/Ser235 region, recognized by AT180, there was more activity this time of AT180 in the presence of LPS. However, the same did not happen in the Ser396/Ser404 region that was recognized by PHD finger protein 1 (PHF-1), where the sample with LPS was not altered to a greater extent compared to that which was administered PBS [66]. TLR4's activation has proven to initiate the TAU-mediated pathologies in a more powerful manner in aged 3xTg-AD mice (more than 12 months of age), which means that the influence of TAU over inflammatory mechanisms grows stronger with age. Older groups of 3xTg-AD, which received a chronic LPS treatment, showed TAU phosphorylation in AT8, AT180, and PHF-1 epitopes, as well as TAU accumulation and aggregation as neurofibrillary tangles and cognitive deterioration, appearing, though, no changes in platelet saturation of Aβ. In this tested, aged animals, TAU pathology modulation induced by TLR4 is principally dominated by GSK3β (glycogen synthase kinase-3ß), the latter data were verified through the inhibition with lithium of GSK3β, where a reduction was observed of the phosphorylation of TAU and the accumulation in its insoluble form together with the reversal of memory problems [67].

Another possible route deduced in a study done in the brains of patients with early onset of Alzheimer's disease (FAD) with the Swedish mutation for APP, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) three well-known taupathies, which presented PS3 positive vesicles in the frontal cortex, which indicates that autophagic vesicles accumulated in the said location. In addition, LAMP1 (lysosomal-associated membrane protein 1) lysosomal markers were found in FAD and CBD, and cathepsin in the three mentioned diseases. Thus, this study presents a possible role of the autophagy-lysosome pathway that would contribute to the development of primary taupathies as well as FAD [68]. The unbalanced increase in IL-1β expression in 3xTg-AD models generated inverse effects in amyloid-based pathologies and TAU accumulation, by increasing the addition of its pathological forms while decreasing the total quantities of Aβ plaques. The elimination of such plaques is powered up by the effects of IL-1β in an increase in Aβ plaque surrounding activated microglia. This process also augments the proinflammatory status, in a directly proportional intensity to age, by means of its elimination. In

**89**

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

turn, it was also found in this experiment that it generates the activation of GSK3β and p38-MAPK, which leads to a higher level of phosphorylation in TAU [69]. It has been demonstrated in an experiment carried out in 3xTg-AD transgenic mice that the inhibition of IL-1 signaling decreases the activation of the kinases CDK5/p25, GSK3β, and p38-MAPK, as well as reduces the phosphorylation levels of TAU [66]. On the other hand, the blockade of IL-1R showed that it altered the inflammatory responses of the brain (related to a lower activity of NF-κB), reduces cognitive deficits, and notably attenuates the pathology attributed to TAU, and decreases the oligomeric and fibrillary forms of Aβ. Similarly, it was found that there was a reduction of the cytokine derived from astrocytes, S100β, and in neuronal signaling with Wnt/β-catenin in 3xTg-AD brains [66, 70]. In addition to the complex connection between inflammation and AD, it has been shown that opposite effects can be seen in Aβ and TAU produced with inflammation. For example, it was shown that the main risk factor for Alzheimer's disease, aging, seems to cause a decrease in the levels of sirtuin 1 (SIRT1), which is related to microglial aging. Thus, this deficiency in the microglial SIRT1 with age results in an excessive production of IL-1β, which in turn causes pathology through TAU in addition to cognitive deficits. The deficiency of microglial SIRT1 induces a hypomethylation of specific loci CpG

in the promoter for IL-1β, with elevation of IL-1β transcription [71].

hyperphosphorylation will probably produce better clinical results.

Analogous to microglia, astrocytes play multiple roles in the organization and maintenance of brain structure and function. Multiple studies show that astrocytes dynamically modulate information processing, signal transmission, neural and synaptic plasticity. As well as, homeostasis of the blood-brain barrier, and its role in immune responses. The evidence shows us how during cerebral ischemia, it acts as a protector, whereas against inflammation mediated by the lipopolysaccharide of *Escherichia coli*, its intervention seems to be harmful [77]. In the cells of the retina, however, it has been proven that through the production of lipoxins, it has

*5.2.3 Astrocytes and inflammation*

Parallel studies affirm what was previously stated. For example, CX3CR1 deficiency in mouse models of amyloidosis mitigates the accumulation of Aβ by altering microglial activation and promoting microglial phagocytosis [65, 72]. On the other hand, blockade of CX3CR1 signaling increases IL-1β/p38-MAPK-mediated TAU phosphorylation in the hTau taupathy model [43]. The genetic suppression of CX3CL1 anchored to the membrane, ligand of CX3CR1, in models of amyloid pathology and taupathy in the APP/PS1 mouse models also reduces the deposition of Aβ through the increase of phagocytosis mediated by microglia and at the same time induces phosphorylation of neuronal TAU [73], thus having similar effects as in the deficiency of the microglial receptor CX3CR1, as shown above. In addition, it was already studied that a loss of function was mediated by mutations of progranulin, which has been associated with frontotemporal dementia [74], and results in an increase in the activation signal of tyrosine kinase binding protein TYRO (TYROBP) and Aβ microglial phagocytosis in the APP/PS1 mouse model, while TAU pathology increases in mice expressing the human TA30 PIL mutation [75]. Obviously, these opposite effects induced by the immune signal in the accumulation of Aβ and TAU raise concerns as to the direction of the therapies relating to mitigate one or both of these effects by activating or inhibiting inflammation in the context of Alzheimer's disease. As we have seen in previous experiments, it is already known clinically and is explicitly stated in a research that TAU levels correlate better with cognitive deficits observed during the disease process [76]. The development of strategies to modulate the immune system to act in the deposition of Aβ and TAU

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

### *Astrocytes and Inflammatory Processes in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.88701*

*Glia in Health and Disease*

showed high levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when they were grown together with microglia Cx3cr1<sup>−</sup>/<sup>−</sup> treated with LPS. Second,

a population of positive neurons for TAU protein phospho-S199 (AT8) in the dentate gyrus is also positive for (CC3) for mice treated with Cx3cr1<sup>−</sup>/<sup>−</sup>. Third, the genetic deficiency of TAU in Cx3cr1<sup>−</sup>/<sup>−</sup> mice resulted in reduced microglial activation, which altered the expression of inflammatory genes in those neurons positive for CC3 compared to Cx3cr1<sup>−</sup>/<sup>−</sup> mice [44]. These results suggest that pathological changes in TAU mediate the neurotoxicity induced by inflammation, while Mapt deficiency is neuroprotective. It was proposed that this earlier phenomenon was probably associated with the indirect reduction of microglial activity due to the decrease in the production of pathological species of TAU, observed in a transgenic mouse model rTg4510, which expresses the mutation in P310L (4R0N TauP301L) and initiates taupathy within 3–5 months. Brain stimulation of TLR4 by LPS in the aforementioned mouse model also produces activation of microglia and phosphorylation of TAU [65]. In another investigation using the 3xTg-AD transgenic mouse model, which develops both Aβ and taupathies, chronic treatment with LPS results in phosphorylation of CDK5-dependent TAU without affecting Aβ levels in adult animals (~6 months old). TAU phosphorylation was observed by immunohistochemistry techniques when treated with LPS and PBS samples of the aforementioned 3xTg-AD mice by two tests: in the first one in the Ser202/Thr205 residues that were recognized by AT8, they presented up to twice as much AT8 activity in the samples treated with LPS as those that were administered PBS; the second test detected that in the Thr231/Ser235 region, recognized by AT180, there was more activity this time of AT180 in the presence of LPS. However, the same did not happen in the Ser396/Ser404 region that was recognized by PHD finger protein 1 (PHF-1), where the sample with LPS was not altered to a greater extent compared to that which was administered PBS [66]. TLR4's activation has proven to initiate the TAU-mediated pathologies in a more powerful manner in aged 3xTg-AD mice (more than 12 months of age), which means that the influence of TAU over inflammatory mechanisms grows stronger with age. Older groups of 3xTg-AD, which received a chronic LPS treatment, showed TAU phosphorylation in AT8, AT180, and PHF-1 epitopes, as well as TAU accumulation and aggregation as neurofibrillary tangles and cognitive deterioration, appearing, though, no changes in platelet saturation of Aβ. In this tested, aged animals, TAU pathology modulation induced by TLR4 is principally dominated by GSK3β (glycogen synthase kinase-3ß), the latter data were verified through the inhibition with lithium of GSK3β, where a reduction was observed of the phosphorylation of TAU and the accumulation in its insoluble form

together with the reversal of memory problems [67].

Another possible route deduced in a study done in the brains of patients with early onset of Alzheimer's disease (FAD) with the Swedish mutation for APP, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) three well-known taupathies, which presented PS3 positive vesicles in the frontal cortex, which indicates that autophagic vesicles accumulated in the said location. In addition, LAMP1 (lysosomal-associated membrane protein 1) lysosomal markers were found in FAD and CBD, and cathepsin in the three mentioned diseases. Thus, this study presents a possible role of the autophagy-lysosome pathway that would contribute to the development of primary taupathies as well as FAD [68]. The unbalanced increase in IL-1β expression in 3xTg-AD models generated inverse effects in amyloid-based pathologies and TAU accumulation, by increasing the addition of its pathological forms while decreasing the total quantities of Aβ plaques. The elimination of such plaques is powered up by the effects of IL-1β in an increase in Aβ plaque surrounding activated microglia. This process also augments the proinflammatory status, in a directly proportional intensity to age, by means of its elimination. In

**88**

turn, it was also found in this experiment that it generates the activation of GSK3β and p38-MAPK, which leads to a higher level of phosphorylation in TAU [69].

It has been demonstrated in an experiment carried out in 3xTg-AD transgenic mice that the inhibition of IL-1 signaling decreases the activation of the kinases CDK5/p25, GSK3β, and p38-MAPK, as well as reduces the phosphorylation levels of TAU [66]. On the other hand, the blockade of IL-1R showed that it altered the inflammatory responses of the brain (related to a lower activity of NF-κB), reduces cognitive deficits, and notably attenuates the pathology attributed to TAU, and decreases the oligomeric and fibrillary forms of Aβ. Similarly, it was found that there was a reduction of the cytokine derived from astrocytes, S100β, and in neuronal signaling with Wnt/β-catenin in 3xTg-AD brains [66, 70]. In addition to the complex connection between inflammation and AD, it has been shown that opposite effects can be seen in Aβ and TAU produced with inflammation. For example, it was shown that the main risk factor for Alzheimer's disease, aging, seems to cause a decrease in the levels of sirtuin 1 (SIRT1), which is related to microglial aging. Thus, this deficiency in the microglial SIRT1 with age results in an excessive production of IL-1β, which in turn causes pathology through TAU in addition to cognitive deficits. The deficiency of microglial SIRT1 induces a hypomethylation of specific loci CpG in the promoter for IL-1β, with elevation of IL-1β transcription [71].

Parallel studies affirm what was previously stated. For example, CX3CR1 deficiency in mouse models of amyloidosis mitigates the accumulation of Aβ by altering microglial activation and promoting microglial phagocytosis [65, 72]. On the other hand, blockade of CX3CR1 signaling increases IL-1β/p38-MAPK-mediated TAU phosphorylation in the hTau taupathy model [43]. The genetic suppression of CX3CL1 anchored to the membrane, ligand of CX3CR1, in models of amyloid pathology and taupathy in the APP/PS1 mouse models also reduces the deposition of Aβ through the increase of phagocytosis mediated by microglia and at the same time induces phosphorylation of neuronal TAU [73], thus having similar effects as in the deficiency of the microglial receptor CX3CR1, as shown above. In addition, it was already studied that a loss of function was mediated by mutations of progranulin, which has been associated with frontotemporal dementia [74], and results in an increase in the activation signal of tyrosine kinase binding protein TYRO (TYROBP) and Aβ microglial phagocytosis in the APP/PS1 mouse model, while TAU pathology increases in mice expressing the human TA30 PIL mutation [75]. Obviously, these opposite effects induced by the immune signal in the accumulation of Aβ and TAU raise concerns as to the direction of the therapies relating to mitigate one or both of these effects by activating or inhibiting inflammation in the context of Alzheimer's disease. As we have seen in previous experiments, it is already known clinically and is explicitly stated in a research that TAU levels correlate better with cognitive deficits observed during the disease process [76]. The development of strategies to modulate the immune system to act in the deposition of Aβ and TAU hyperphosphorylation will probably produce better clinical results.

### *5.2.3 Astrocytes and inflammation*

Analogous to microglia, astrocytes play multiple roles in the organization and maintenance of brain structure and function. Multiple studies show that astrocytes dynamically modulate information processing, signal transmission, neural and synaptic plasticity. As well as, homeostasis of the blood-brain barrier, and its role in immune responses. The evidence shows us how during cerebral ischemia, it acts as a protector, whereas against inflammation mediated by the lipopolysaccharide of *Escherichia coli*, its intervention seems to be harmful [77]. In the cells of the retina, however, it has been proven that through the production of lipoxins, it has

an anti-inflammatory and neuroprotective effect against acute and chronic lesions [78]. Similarly, the role of the cytokine IL-33 produced by astrocytes has recently been demonstrated for the microglial approach to the synaptic terminals, as well as the development of neural circuits [79]. In previously mentioned studies describing the action of IL-1α<sup>+</sup> , it is concluded that there is also a correlation between IL-1α and the greater number of GFAP+ astrocytes (GFAP-immunoreactive astrocytes) [80]. On the other hand, it has been demonstrated in an experiment carried out in mice with multiple sclerosis TNF-α alters synaptic transmission and produces interferences at the cognitive level [81]. Other studies have shown that the activation of certain transcription factors are also involved, developing protective effects (STAT3) [82] or injurious effects (NF-κB) [83] (**Figure 2**).

### *5.2.4 Role of astrocytes in amyloid production*

The role of astrocytes in the amyloidogenic pathway is currently being widely studied. For a long time, it was thought that neurons were the only type of cell that expressed high levels of BACE1 and, therefore, that neuron was the only type of cell capable of producing Aβ [84]. However, studies have shown that astrocytes express BACE1 at sufficient levels to generate Aβ, and that expression can be increased by cell stress [85–89]. In addition, stressors can upregulate the expression of APP and, therefore, the secretion of Aβ. In contrast, the effect of cellular stress on the activity of γ-secretase in astrocytes has not yet been fully clarified.

The production of Aβ will lead to activation of the microglia and astrocytes in order to get rid of these brain waste products [90–92]. Similarly, genetic studies have identified polymorphisms of a single nucleotide in inflammatory genes that are associated with the risk of AD, highlighting the role of inflammation in AD [86, 93–95]. In addition, it has been observed that patients with Alzheimer's disease have more proinflammatory cytokines and activated inflammasomes [96]. As demonstrated in studies that claim an increase in both glial fibrillary acid protein (GFAP) and S100β expression, they lead to greater astrogliosis in postmortem tissues of human patients and experimental models in mice. In the same way, a correlation has been found, in different studies, between the degree of astrogliosis and cognitive deterioration [32, 96, 97]. As astrocytes substantially exceed the number of neurons in the brain, the identification of cellular environment factors (such as inflammation), which promote the production of astrocytic Aβ, could redefine our therapeutic targets when it comes to fighting Alzheimer's disease.

**91**

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

The cytokine S100β is known to be an important neurotrophic agent during fetal

, identified with activated astrocytes,

development, both in neuroblasts and in the glia [98]. In addition to this known function, it is known that it directly contributes to the activation and subsequent gliosis, stimulating the proliferation of astrocytes and inducing morphological changes [70]. Furthermore, the IL-1 produced in the microglia, is the responsible

The distribution of S100β contained in activated astrocytes by ELISA and immunohistochemistry was studied, as shown by many, few, or no neuritic plaques in the context of Alzheimer's disease. Postmortem samples were obtained from both patients diagnosed with AD and control patients from the hippocampus, temporal lobes, frontal lobes, occipital lobes, brain stem, and cerebellum. The results indi-

was higher around the neuritic plaques in certain areas of the brain. By order, the concentration was found to be more remarkable in the hippocampus > temporal lobe > frontal lobe > occipital lobe > protuberance, and no neuritic plaques were found in the cerebellum. The importance of these results lies in the fact that the regulatory role of the cytokine S100β contributes to the development or maintenance of dystrophic neurites observed in neuritic plaques. Furthermore, overexpression of S100β shows that it has been related to a higher degree of dysfunction and neural

loss in AD caused by an intracellular increase in calcium levels [70].

patterns present in the different pathological models mentioned [99].

In astrocytes, the first morphological change is the process of hypertrophy that is intimately related to the greater expression of intermediate filaments, attributed to the action of GFAP [99]. Although the consequences of GFAP expression are not fully understood, it is known that they have a determining role in limiting the creation of Aβ plaques. The impact of this reactive astrogliosis is complex: reactive astrogliosis can be both harmful or beneficial at the time the cells are affected. Reagent astrocytes will surround the Aβ plaques and will express receptors such as receptor for advanced glycation end products (RAGE), receptor-like LDL protein (low-density lipoprotein), membrane-associated proteinglycans, as well as receptor-like scavenger receptors to bind to Aβ [100]. Reactive astrocytes will be neurotoxic when they generate

Astrogliosis occurs in the presence of a central nervous system lesion.

Inflammatory mediators made by microglia, neurons, oligodendrocytes, endothelial cells, leukocytes, and other astrocytes initially cause astrocytes to become reactive [77]. To better understand the process of astrogliosis, we must bear in mind that a series of changes occur at the phenotype level of astrocytes, which induce a specific expression. This was demonstrated in an experiment using arrays (Affymetrix GeneChip arrays) to define the genetic expression of different populations of reactive astrocytes isolated at different time periods using two models of injury (neuroinflammation and ischemic stroke) in mice. It was observed that this reactive gliosis had a rapid, but rapidly diminished, pattern of induction of gene expression after damage, where Lcn2 and Sertapina3n were identified as the major markers of reactive astrocytes. It was also seen that the pattern of expression experienced during ischemic stroke had a protective profile, whereas in the population of mice in which neuroinflammation was induced by the use of LPS, it turned out to be, on the contrary, detrimental [77]. Moreover, using high-density microarray, reactive astrocytes also produced detrimental effects (in vitro models from multiple sclerosis, neoplasms and stroke), and was identified up to 44 different transcription

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

*5.2.5 S100β and inflammation*

for the overproduction of S100β.

*5.2.6 Astrogliosis*

cated that the density of cells that were S100β<sup>+</sup>

### *5.2.5 S100β and inflammation*

*Glia in Health and Disease*

the action of IL-1α<sup>+</sup>

**Figure 2.**

and the greater number of GFAP+

*Implication of astrocytes in inflammation.*

an anti-inflammatory and neuroprotective effect against acute and chronic lesions [78]. Similarly, the role of the cytokine IL-33 produced by astrocytes has recently been demonstrated for the microglial approach to the synaptic terminals, as well as the development of neural circuits [79]. In previously mentioned studies describing

[80]. On the other hand, it has been demonstrated in an experiment carried out in mice with multiple sclerosis TNF-α alters synaptic transmission and produces interferences at the cognitive level [81]. Other studies have shown that the activation of certain transcription factors are also involved, developing protective effects

The role of astrocytes in the amyloidogenic pathway is currently being widely studied. For a long time, it was thought that neurons were the only type of cell that expressed high levels of BACE1 and, therefore, that neuron was the only type of cell capable of producing Aβ [84]. However, studies have shown that astrocytes express BACE1 at sufficient levels to generate Aβ, and that expression can be increased by cell stress [85–89]. In addition, stressors can upregulate the expression of APP and, therefore, the secretion of Aβ. In contrast, the effect of cellular stress on the activity

The production of Aβ will lead to activation of the microglia and astrocytes in order to get rid of these brain waste products [90–92]. Similarly, genetic studies have identified polymorphisms of a single nucleotide in inflammatory genes that are associated with the risk of AD, highlighting the role of inflammation in AD [86, 93–95]. In addition, it has been observed that patients with Alzheimer's disease have more proinflammatory cytokines and activated inflammasomes [96]. As demonstrated in studies that claim an increase in both glial fibrillary acid protein (GFAP) and S100β expression, they lead to greater astrogliosis in postmortem tissues of human patients and experimental models in mice. In the same way, a correlation has been found, in different studies, between the degree of astrogliosis and cognitive deterioration [32, 96, 97]. As astrocytes substantially exceed the number of neurons in the brain, the identification of cellular environment factors (such as inflammation), which promote the production of astrocytic Aβ, could redefine our therapeu-

(STAT3) [82] or injurious effects (NF-κB) [83] (**Figure 2**).

of γ-secretase in astrocytes has not yet been fully clarified.

tic targets when it comes to fighting Alzheimer's disease.

*5.2.4 Role of astrocytes in amyloid production*

, it is concluded that there is also a correlation between IL-1α

astrocytes (GFAP-immunoreactive astrocytes)

**90**

The cytokine S100β is known to be an important neurotrophic agent during fetal development, both in neuroblasts and in the glia [98]. In addition to this known function, it is known that it directly contributes to the activation and subsequent gliosis, stimulating the proliferation of astrocytes and inducing morphological changes [70]. Furthermore, the IL-1 produced in the microglia, is the responsible for the overproduction of S100β.

The distribution of S100β contained in activated astrocytes by ELISA and immunohistochemistry was studied, as shown by many, few, or no neuritic plaques in the context of Alzheimer's disease. Postmortem samples were obtained from both patients diagnosed with AD and control patients from the hippocampus, temporal lobes, frontal lobes, occipital lobes, brain stem, and cerebellum. The results indicated that the density of cells that were S100β<sup>+</sup> , identified with activated astrocytes, was higher around the neuritic plaques in certain areas of the brain. By order, the concentration was found to be more remarkable in the hippocampus > temporal lobe > frontal lobe > occipital lobe > protuberance, and no neuritic plaques were found in the cerebellum. The importance of these results lies in the fact that the regulatory role of the cytokine S100β contributes to the development or maintenance of dystrophic neurites observed in neuritic plaques. Furthermore, overexpression of S100β shows that it has been related to a higher degree of dysfunction and neural loss in AD caused by an intracellular increase in calcium levels [70].

### *5.2.6 Astrogliosis*

Astrogliosis occurs in the presence of a central nervous system lesion. Inflammatory mediators made by microglia, neurons, oligodendrocytes, endothelial cells, leukocytes, and other astrocytes initially cause astrocytes to become reactive [77]. To better understand the process of astrogliosis, we must bear in mind that a series of changes occur at the phenotype level of astrocytes, which induce a specific expression. This was demonstrated in an experiment using arrays (Affymetrix GeneChip arrays) to define the genetic expression of different populations of reactive astrocytes isolated at different time periods using two models of injury (neuroinflammation and ischemic stroke) in mice. It was observed that this reactive gliosis had a rapid, but rapidly diminished, pattern of induction of gene expression after damage, where Lcn2 and Sertapina3n were identified as the major markers of reactive astrocytes. It was also seen that the pattern of expression experienced during ischemic stroke had a protective profile, whereas in the population of mice in which neuroinflammation was induced by the use of LPS, it turned out to be, on the contrary, detrimental [77]. Moreover, using high-density microarray, reactive astrocytes also produced detrimental effects (in vitro models from multiple sclerosis, neoplasms and stroke), and was identified up to 44 different transcription patterns present in the different pathological models mentioned [99].

In astrocytes, the first morphological change is the process of hypertrophy that is intimately related to the greater expression of intermediate filaments, attributed to the action of GFAP [99]. Although the consequences of GFAP expression are not fully understood, it is known that they have a determining role in limiting the creation of Aβ plaques. The impact of this reactive astrogliosis is complex: reactive astrogliosis can be both harmful or beneficial at the time the cells are affected. Reagent astrocytes will surround the Aβ plaques and will express receptors such as receptor for advanced glycation end products (RAGE), receptor-like LDL protein (low-density lipoprotein), membrane-associated proteinglycans, as well as receptor-like scavenger receptors to bind to Aβ [100]. Reactive astrocytes will be neurotoxic when they generate

reactive oxygen species or proinflammatory cytokines [101]. In order to understand the role of cerebral gliosis, the balance between the mechanisms that orient toward the neuroprotective or neurotoxic effect must be taken into account.

Patients with AD showed reactive astrocytes as shown by PET images [102, 103] and also, before the formation of plaques in transgenic APP mice [104]. Reactive astrocytes, depending on the level of gliotransmitters (including glutamate, ATP, serine-d and GABA) can produce inhibition of neuronal activity [105]. There is a consensus that the role of GABA is to protect neuronal cells in the brain [106]. In the amyloid plaques, an increase in the GABA protein has been detected in the reactive astrocytes that surround the plaques and that cause a greater release in the extracellular space [105]. It has been studied that these investigations have their limitations, since normally studies are carried out in mouse models, while in the human species there are many more processes to take into account [107].

### *5.2.7 Astrocytes, chemokines, and cytokines*

Astrocytes can sometimes release reactive oxygen species (ROS), chemokines, or cytokines (CCL3, CCL4, CCL1, IL-1, for example) [108, 109]. Normally, those responsible for expressing these substances are going to be the so-called reactive astrocytes that cause functional changes by the expression of genes and the formation of glial scars that can be beneficial [81] or harmful to cells [82]. By using lipopolysaccharide (LPS) as an inducer, astrocytes increase the expression of many genes (C3a, C3b, C5, lectin) in the complement cascade that can be harmful [82]. On the other hand, it has been shown that positive regulation of trophic factors after ischemic damage is a protective mechanism [81]. Following the same line, inflammation is an essential factor in the progression of Alzheimer's disease in humans, demonstrating that this inflammation promotes the activation of microglia and an increase in reactive astrocytes that change their shape and increase the ramifications to go to the place of injury [110].

Relating astrogliosis to inflammation, both resting astrocytes and reactive astrocytes can secrete numerous cytokines capable of inducing inflammation, such as IFNγ, IL-1β, TNFα, IL-6, and TGFβ [37, 111–113]. IFNγ is a potent regulatory cytokine that activates microglia and promotes inflammation in the brain and is overproduced in the brains of patients with AD [114] both by microglia and astrocytes, despite which it is produced in the first instance by T cells [115, 116]. On the other hand, TNFα is a cytokine involved in the acute phase of inflammation and is also elevated in the serum, cerebral cortex, and cerebrospinal fluid of patients with AD [117]. In a study conducted by scientists at the Rostkamp Institute of the Department of Psychiatry at the University of South Florida, it was demonstrated in mice that those which were deficient in CD40, which is a gene that codes for the receptor TNF (Tumor Necrosis Factor), had a reduced activity of BACE, Aβ, and gliosis in comparison to the samples that presented normal quantities of CD40 [118]. IL-6 can have both proinflammatory and antiinflammatory effects and has also been found elevated in plasma, cerebrospinal fluid, and in the brains of Alzheimer's patients [39, 119–122]. IL-1β constitutes one of the first cytokines secreted in response to lesions, as it is an important mediator of proliferation, differentiation, and apoptosis. The concentration of the said cytokine has been increased near the sites where the amyloid plaques are located [38–40].

A specific polymorphism in the transforming growth factor β1 (TGFβ1), an immunosuppressive cytokine, is also related to the risk of developing AD [123]. In addition, postmortem brains analyzed from Alzheimer's patients contained higher levels of TGFβ, specifically in their plaques, suggesting their

**93**

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

involvement in the same disease [124, 125]. Other studies performed in older mice that overexpress TGFβ in astrocytes promoted the deposition of Aβ, and those astrocytes containing TGFβ1 were located in the vicinity of the Aβ deposits in those mice that overexpressed APP with Swedish mutation [126–129]. Finally, astrocytes release purines that can influence the development of AD and activate the production of inflammatory proteins, decreasing anti-inflam-

As it has been already mentioned before, APP is the substrate prior to Aβ after erroneous processing by the BACE1 and γ-secretase enzymes. The expression of APP by astrocytes has been demonstrated by the identification of APP695, APP751, and APP770 mRNAs found in non-neuronal cells [126] and in rat astrocytes [130]. In addition, it has been shown that multiple proinflammatory cytokines upregulate APP in both mouse and human brains (investigating neuroblastoma cells and other non-neuronal cells such as human astrocytes) [131]. These findings imply that neuroinflammation in reactive astrocytes expresses higher levels of APP than when mice are at rest and they, therefore, may end up producing more β amyloid. Similarly, in APP/PS1 mice, an increase in chemokines and their receptors, compared to wild type mice, such as CCL3, CCL4, CCL1 and the receptors CCR5 and

Several studies have shown that the transcription factor for APP (AP-1) is found in the promoter region of many of the acute phase proteins of inflammation that are induced by the cytokines IL-1β and IL-6, suggesting that the expression of APP is regulated in the same way by these specific cytokines [132, 133]. Moreover, astrocytes stimulated with different combinations of cytokines (LPS + IFNγ, TNFα + IFNγ, and TNFα + IL-1β + IFNγ) increased the expression of APP [89].

The type of tumor and its location are determined by age; for example, infratentorial astrocytoma and midline tumors, such as medulloblastoma and pinealoma, anaplastic astrocytoma, and glioblastoma predominate in adulthood [134]. Although meningiomas are the most frequently detected in the series of autopsies, glioblastomas are the most frequently detected in the brain. Some brain tumors such as schwannoma, sarcoma, glioma, and meningioma are detected after the patient has been exposed to cancer therapy with chemotherapy and/or radiotherapy. Until now it was thought that only glial cells and stem cells were responsible for the emergence of glioblastoma, but it is now known that mature neurons can also induce this type of cancer. This is due to the fact that these cells revert to an undifferentiated state that is

Radial glia are stem cells that develop from a progenitor stem cell in the embryo

and adult brain [136]. The neuroblastoma cells are radial glia or precursors of astrocytes that can develop before their differentiation into neurons. In the same way, glial cells can also develop different types of cells besides neurons such as oligodendroglia and astrocytes [137]. All these types of cells can turn into cancer and affect the normal function of the brain. Then, astrocytes and their progenitor cells can cause cancer and destroy many functions in the brain. It is interesting to note that in some astrocytomas, the patients increase their cognitive capacity, memory, and spatial vision, before the disease begins and also when the cancer is present [138], which makes us think and throws more evidence to the role of astrocytes in

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

matory proteins [108].

CCR8 was detected [108].

*5.2.9 Astrocytes and cancer*

directed to proliferate as an uncontrolled tumor [135].

modulating cognitive brain functions or memory.

*5.2.8 Astrocytes and expression of APP*

involvement in the same disease [124, 125]. Other studies performed in older mice that overexpress TGFβ in astrocytes promoted the deposition of Aβ, and those astrocytes containing TGFβ1 were located in the vicinity of the Aβ deposits in those mice that overexpressed APP with Swedish mutation [126–129]. Finally, astrocytes release purines that can influence the development of AD and activate the production of inflammatory proteins, decreasing anti-inflammatory proteins [108].

### *5.2.8 Astrocytes and expression of APP*

*Glia in Health and Disease*

reactive oxygen species or proinflammatory cytokines [101]. In order to understand the role of cerebral gliosis, the balance between the mechanisms that orient toward

Patients with AD showed reactive astrocytes as shown by PET images [102, 103] and also, before the formation of plaques in transgenic APP mice [104]. Reactive astrocytes, depending on the level of gliotransmitters (including glutamate, ATP, serine-d and GABA) can produce inhibition of neuronal activity [105]. There is a consensus that the role of GABA is to protect neuronal cells in the brain [106]. In the amyloid plaques, an increase in the GABA protein has been detected in the reactive astrocytes that surround the plaques and that cause a greater release in the extracellular space [105]. It has been studied that these investigations have their limitations, since normally studies are carried out in mouse models, while in the human species

Astrocytes can sometimes release reactive oxygen species (ROS), chemokines, or cytokines (CCL3, CCL4, CCL1, IL-1, for example) [108, 109]. Normally, those responsible for expressing these substances are going to be the so-called reactive astrocytes that cause functional changes by the expression of genes and the formation of glial scars that can be beneficial [81] or harmful to cells [82]. By using lipopolysaccharide (LPS) as an inducer, astrocytes increase the expression of many genes (C3a, C3b, C5, lectin) in the complement cascade that can be harmful [82]. On the other hand, it has been shown that positive regulation of trophic factors after ischemic damage is a protective mechanism [81]. Following the same line, inflammation is an essential factor in the progression of Alzheimer's disease in humans, demonstrating that this inflammation promotes the activation of microglia and an increase in reactive astrocytes that change their shape and increase the

Relating astrogliosis to inflammation, both resting astrocytes and reactive astrocytes can secrete numerous cytokines capable of inducing inflammation, such as IFNγ, IL-1β, TNFα, IL-6, and TGFβ [37, 111–113]. IFNγ is a potent regulatory cytokine that activates microglia and promotes inflammation in the brain and is overproduced in the brains of patients with AD [114] both by microglia and astrocytes, despite which it is produced in the first instance by T cells [115, 116]. On the other hand, TNFα is a cytokine involved in the acute phase of inflammation and is also elevated in the serum, cerebral cortex, and cerebrospinal fluid of patients with AD [117]. In a study conducted by scientists at the Rostkamp Institute of the Department of Psychiatry at the University of South Florida, it was demonstrated in mice that those which were deficient in CD40, which is a gene that codes for the receptor TNF (Tumor Necrosis Factor), had a reduced activity of BACE, Aβ, and gliosis in comparison to the samples that presented normal quantities of CD40 [118]. IL-6 can have both proinflammatory and antiinflammatory effects and has also been found elevated in plasma, cerebrospinal fluid, and in the brains of Alzheimer's patients [39, 119–122]. IL-1β constitutes one of the first cytokines secreted in response to lesions, as it is an important mediator of proliferation, differentiation, and apoptosis. The concentration of the said cytokine has been increased near the sites where the amyloid plaques are located

A specific polymorphism in the transforming growth factor β1 (TGFβ1), an immunosuppressive cytokine, is also related to the risk of developing AD [123]. In addition, postmortem brains analyzed from Alzheimer's patients contained higher levels of TGFβ, specifically in their plaques, suggesting their

the neuroprotective or neurotoxic effect must be taken into account.

there are many more processes to take into account [107].

*5.2.7 Astrocytes, chemokines, and cytokines*

ramifications to go to the place of injury [110].

**92**

[38–40].

As it has been already mentioned before, APP is the substrate prior to Aβ after erroneous processing by the BACE1 and γ-secretase enzymes. The expression of APP by astrocytes has been demonstrated by the identification of APP695, APP751, and APP770 mRNAs found in non-neuronal cells [126] and in rat astrocytes [130]. In addition, it has been shown that multiple proinflammatory cytokines upregulate APP in both mouse and human brains (investigating neuroblastoma cells and other non-neuronal cells such as human astrocytes) [131]. These findings imply that neuroinflammation in reactive astrocytes expresses higher levels of APP than when mice are at rest and they, therefore, may end up producing more β amyloid. Similarly, in APP/PS1 mice, an increase in chemokines and their receptors, compared to wild type mice, such as CCL3, CCL4, CCL1 and the receptors CCR5 and CCR8 was detected [108].

Several studies have shown that the transcription factor for APP (AP-1) is found in the promoter region of many of the acute phase proteins of inflammation that are induced by the cytokines IL-1β and IL-6, suggesting that the expression of APP is regulated in the same way by these specific cytokines [132, 133]. Moreover, astrocytes stimulated with different combinations of cytokines (LPS + IFNγ, TNFα + IFNγ, and TNFα + IL-1β + IFNγ) increased the expression of APP [89].

### *5.2.9 Astrocytes and cancer*

The type of tumor and its location are determined by age; for example, infratentorial astrocytoma and midline tumors, such as medulloblastoma and pinealoma, anaplastic astrocytoma, and glioblastoma predominate in adulthood [134]. Although meningiomas are the most frequently detected in the series of autopsies, glioblastomas are the most frequently detected in the brain. Some brain tumors such as schwannoma, sarcoma, glioma, and meningioma are detected after the patient has been exposed to cancer therapy with chemotherapy and/or radiotherapy. Until now it was thought that only glial cells and stem cells were responsible for the emergence of glioblastoma, but it is now known that mature neurons can also induce this type of cancer. This is due to the fact that these cells revert to an undifferentiated state that is directed to proliferate as an uncontrolled tumor [135].

Radial glia are stem cells that develop from a progenitor stem cell in the embryo and adult brain [136]. The neuroblastoma cells are radial glia or precursors of astrocytes that can develop before their differentiation into neurons. In the same way, glial cells can also develop different types of cells besides neurons such as oligodendroglia and astrocytes [137]. All these types of cells can turn into cancer and affect the normal function of the brain. Then, astrocytes and their progenitor cells can cause cancer and destroy many functions in the brain. It is interesting to note that in some astrocytomas, the patients increase their cognitive capacity, memory, and spatial vision, before the disease begins and also when the cancer is present [138], which makes us think and throws more evidence to the role of astrocytes in modulating cognitive brain functions or memory.

### **5.3 Protective role of astrocytes**

### *5.3.1 Oxidative stress, AD, and the protective role of astrocytes against oxidative stress*

Hydrogen peroxide (H2O2), superoxide (O2 <sup>−</sup>) and hydroxyl radicals (OH<sup>−</sup>) are the aforementioned reactive oxygen species (ROS). Due to the rate of oxidative metabolism, the SNC is especially susceptible to the damage suffered by them [139]. Under stable physiological conditions, the homeostasis of ROS is under control and this is crucial for the proper organic functions. ROS stimulates the proliferation of brain cells, but at high concentrations, ROS has harmful effects on different cellular structures such as membranes, DNA, and enzymes, which can lead to cell death [140]. The reduction of molecular oxygen is not complete in the respiratory chain, producing ROS continuously and thus affecting different cellular components such as proteins or lipids [141]. To return to the state of physiological equilibrium, the brain has several enzymes, such as peroxidase, superoxide dismutase (SOD), oxidase, and NADPH oxidase (NOX). Neurons have fewer defenses against ROS than astrocytes and cooperation between them is important for neuronal resistance against ROS [30, 142, 143]. Astrocytes contribute to the survival of neurons by detoxifying the ROS enzymes (GSH peroxidase and catalase), increasing antioxidant proteins (GSH or glutathione, vitamin E and ascorbate) and the biogenesis of mitochondria and reducing the activity of metals which can produce redox [31, 144–146]. The most powerful antioxidant protein in the brain is GSH produced by astrocytes and neurons, but neurons depend on astrocytes because they do not use extracellular cysteine efficiently and, therefore, need astrocytes to supply it. In addition, with respect to ascorbic acid, another important antioxidant in the nervous system, we depend on diet to obtain it [147].

Ascorbic acid is released by the astrocytes in the extracellular space and is absorbed by the neurons, where thanks to ascorbate the formation of ROS diminishes and its oxidized form is converted to be recovered by the astrocytes and converted again to ascorbic acid [148]. In addition, the lactate shuttle between astrocytes and neurons is favored by ascorbic acid [149]. Changes in ascorbic acid homeostasis are actually involved in different neurodegenerative diseases and have been analyzed for the treatment of diseases, such as Parkinson's and Huntington's disease [148]. In addition, astrocyte prevention in redox production caused by active metals has been demonstrated as a result of the ability to sequester metals by this cellular type [144].

The increase in ROS levels is related to AD [35], but the effects of antioxidants in clinical studies have been disappointing because the high concentration of antioxidants acts, in many cases, as pro-oxidants. It may also be due to the fact that oxidative stress occurs relatively early in the course of AD and therefore, by its administration at later stages, no results are obtained, or else that the combination of antioxidants does not work in clinical situations in humans [150]. As already shown, astrocytes protect neurons from oxidative stress, producing antioxidant proteins. The toxic amyloid beta peptide causes the production of hydrogen peroxide by astrocytes [151], as shown previously [30], and they release ROS in response to beta amyloid through the pentose-phosphate pathway [151]. In addition, in patients with Alzheimer's disease, there is a fall in the brain cleansing process produced by astrocytes during the sleep period. On the other hand, Haydon showed that the sleep/wake cycle is modulated by astrocytes and is also altered in AD [152]. This finding also demonstrates the close relationship between astrocytes and Alzheimer's disease.

**95**

**Figure 3.**

*Protective effects of astrocytes.*

pathogenesis [30].

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

of different harmful agents and neuronal damage.

*5.3.2 Prejudicial and protective role of astrocytes*

After demonstrating the important role of astrocytes in protecting neurons from oxidative stress, we can deduce that all those conditions mentioned where the astrocyte undergoes changes in its function, beyond the strictly physiological, will result in poor protection of the said neurons and the rest of brain structures in front

As we have seen previously, the role of astrocytes is essentially protective. This

In conclusion, we can see that the role of Aβ, which had been an essential pillar in the etiopathogenesis of Alzheimer's disease for decades, is only one component that gives rise to inflammation, probably mediated by activation of microglia and astrocytes with the goal of getting rid of these brain waste products, although this effect has already been shown to be produced in the same way by different

was also demonstrated by another group finding a mechanism different from those previously studied by cytokines and other inflammatory agents, in which it was shown that the astrocytes surrounding the plates increase the release of ATP in transgenic APP/PS1 mice and this happens because the Ca2+ concentration increases within the cell [153]. This last fact gives us the idea that an increase in ATP in astrocytes and neurons could help to reduce the neuronal death that occurs in Alzheimer's disease. The increase in the production of ATP by the mitochondria of astrocytes could help to recover and reduce the development of the disease [153]. The neurotransmitter glutamate is released by astrocytes in the presence of Aβ and can cause neuronal loss as well as synaptic damage by activation of NMDA receptors [154, 155]. In addition, astrocytes release purines that can influence the development of AD and activate the production of inflammatory proteins, decreasing anti-inflammatory proteins, such as PPAR-γ [108, 156]. This is probably due to the effect of reactive astrogliosis that may have beneficial effects [82] or detrimental effects [83] for neurons, and because these two different reactions depend on the type of triggering of the astrogliosis. Nevertheless, in our laboratory, we demonstrated that astrocytes play a significant role in neuron protection. Astrocytes promote neural viability and improve oxidative stress defense mechanisms with anti-inflammatory effects against Aβ1–42 peptide toxicity. It is probable that the protective effects of astrocytes are related with the mitochondrial biogenesis (**Figure 3**). This could be a complex epigenetic process in Alzheimer's disease

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

*Glia in Health and Disease*

*stress*

obtain it [147].

this cellular type [144].

Alzheimer's disease.

**5.3 Protective role of astrocytes**

Hydrogen peroxide (H2O2), superoxide (O2

*5.3.1 Oxidative stress, AD, and the protective role of astrocytes against oxidative* 

the aforementioned reactive oxygen species (ROS). Due to the rate of oxidative metabolism, the SNC is especially susceptible to the damage suffered by them [139]. Under stable physiological conditions, the homeostasis of ROS is under control and this is crucial for the proper organic functions. ROS stimulates the proliferation of brain cells, but at high concentrations, ROS has harmful effects on different cellular structures such as membranes, DNA, and enzymes, which can lead to cell death [140]. The reduction of molecular oxygen is not complete in the respiratory chain, producing ROS continuously and thus affecting different cellular components such as proteins or lipids [141]. To return to the state of physiological equilibrium, the brain has several enzymes, such as peroxidase, superoxide dismutase (SOD), oxidase, and NADPH oxidase (NOX). Neurons have fewer defenses against ROS than astrocytes and cooperation between them is important for neuronal resistance against ROS [30, 142, 143]. Astrocytes contribute to the survival of neurons by detoxifying the ROS enzymes (GSH peroxidase and catalase), increasing antioxidant proteins (GSH or glutathione, vitamin E and ascorbate) and the biogenesis of mitochondria and reducing the activity of metals which can produce redox [31, 144–146]. The most powerful antioxidant protein in the brain is GSH produced by astrocytes and neurons, but neurons depend on astrocytes because they do not use extracellular cysteine efficiently and, therefore, need astrocytes to supply it. In addition, with respect to ascorbic acid, another important antioxidant in the nervous system, we depend on diet to

Ascorbic acid is released by the astrocytes in the extracellular space and is absorbed by the neurons, where thanks to ascorbate the formation of ROS diminishes and its oxidized form is converted to be recovered by the astrocytes and converted again to ascorbic acid [148]. In addition, the lactate shuttle between astrocytes and neurons is favored by ascorbic acid [149]. Changes in ascorbic acid homeostasis are actually involved in different neurodegenerative diseases and have been analyzed for the treatment of diseases, such as Parkinson's and Huntington's disease [148]. In addition, astrocyte prevention in redox production caused by active metals has been demonstrated as a result of the ability to sequester metals by

The increase in ROS levels is related to AD [35], but the effects of antioxidants

in clinical studies have been disappointing because the high concentration of antioxidants acts, in many cases, as pro-oxidants. It may also be due to the fact that oxidative stress occurs relatively early in the course of AD and therefore, by its administration at later stages, no results are obtained, or else that the combination of antioxidants does not work in clinical situations in humans [150]. As already shown, astrocytes protect neurons from oxidative stress, producing antioxidant proteins. The toxic amyloid beta peptide causes the production of hydrogen peroxide by astrocytes [151], as shown previously [30], and they release ROS in response to beta amyloid through the pentose-phosphate pathway [151]. In addition, in patients with Alzheimer's disease, there is a fall in the brain cleansing process produced by astrocytes during the sleep period. On the other hand, Haydon showed that the sleep/wake cycle is modulated by astrocytes and is also altered in AD [152]. This finding also demonstrates the close relationship between astrocytes and

<sup>−</sup>) and hydroxyl radicals (OH<sup>−</sup>) are

**94**

After demonstrating the important role of astrocytes in protecting neurons from oxidative stress, we can deduce that all those conditions mentioned where the astrocyte undergoes changes in its function, beyond the strictly physiological, will result in poor protection of the said neurons and the rest of brain structures in front of different harmful agents and neuronal damage.

### *5.3.2 Prejudicial and protective role of astrocytes*

As we have seen previously, the role of astrocytes is essentially protective. This was also demonstrated by another group finding a mechanism different from those previously studied by cytokines and other inflammatory agents, in which it was shown that the astrocytes surrounding the plates increase the release of ATP in transgenic APP/PS1 mice and this happens because the Ca2+ concentration increases within the cell [153]. This last fact gives us the idea that an increase in ATP in astrocytes and neurons could help to reduce the neuronal death that occurs in Alzheimer's disease. The increase in the production of ATP by the mitochondria of astrocytes could help to recover and reduce the development of the disease [153]. The neurotransmitter glutamate is released by astrocytes in the presence of Aβ and can cause neuronal loss as well as synaptic damage by activation of NMDA receptors [154, 155]. In addition, astrocytes release purines that can influence the development of AD and activate the production of inflammatory proteins, decreasing anti-inflammatory proteins, such as PPAR-γ [108, 156]. This is probably due to the effect of reactive astrogliosis that may have beneficial effects [82] or detrimental effects [83] for neurons, and because these two different reactions depend on the type of triggering of the astrogliosis. Nevertheless, in our laboratory, we demonstrated that astrocytes play a significant role in neuron protection. Astrocytes promote neural viability and improve oxidative stress defense mechanisms with anti-inflammatory effects against Aβ1–42 peptide toxicity. It is probable that the protective effects of astrocytes are related with the mitochondrial biogenesis (**Figure 3**). This could be a complex epigenetic process in Alzheimer's disease pathogenesis [30].

In conclusion, we can see that the role of Aβ, which had been an essential pillar in the etiopathogenesis of Alzheimer's disease for decades, is only one component that gives rise to inflammation, probably mediated by activation of microglia and astrocytes with the goal of getting rid of these brain waste products, although this effect has already been shown to be produced in the same way by different

**Figure 3.** *Protective effects of astrocytes.*

mediators. In fact, it is related to a greater degree with the progression of the disease and worsening of the symptoms with the increase of phosphorylated TAU in different parts of the brain. In the last years, the therapies have been focused on elimination of the Aβ from the brain of the Alzheimer's patient with poor results [157]. In addition, reactive astrocytes greatly increase NRF-2, which is an antioxidant protein and could produce beneficial effects in Alzheimer's disease [157]. The regulation of oxidative stress or inflammation could help the conservation of neurons located near astrocytes and microglia. Future therapies should be aimed at the development of specific drugs that control the formation of reactive astrocytes and that favor the correct resolution of the inflammation produced by Alzheimer's disease. The study of the genetic mechanisms that predispose to increase amounts of hyperphosphorylated TAU or those that decrease phosphorylation of TAU would be interesting in order to understand cellular mechanisms implicated in AD [157]. Furthermore, the study of the main trigger of this basal chronic inflammation that worsens the clinical symptoms of AD patients, should be crucial to find new therapeutic strategies. Finally, regarding the relationship that exists between the astrocytes and the cells of the nervous system, there would be a greater study of the functions of these cells in the healthy individual. The control of the mechanisms and the understanding of the relationship between astrocytes with other neural cells could help, in the same way, to the therapy of Alzheimer's disease.

## **Abbreviations**


**97**

**Author details**

Constanza Aldasoro and Adrián Jordá

provided the original work is properly cited.

\*Address all correspondence to: lilian.valles@uv.es

Soraya L. Valles\*, Federico Burguet, Antonio Iradi, Martin Aldasoro, Jose M. Vila,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Physiology, School of Medicine, University of Valencia, Spain

*Astrocytes and Inflammatory Processes in Alzheimer's Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

*Astrocytes and Inflammatory Processes in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.88701*

*Glia in Health and Disease*

to the therapy of Alzheimer's disease.

AD Alzheimer's disease IL-1β interleukin 1β

Aβ β-amyloid

LXA4 lipoxin A4 IL-10 interleukin 10 IL-37 interleukin 37

NO nitric oxide

CX3CL1 fraktalkina

SIT1 sirtuin 1

NF-ᴋB nuclear factor ᴋB

TLR4 toll like receptor 4

TNF-α tumor necrosis factor α

CNS central nervous system PNS peripheral nervous system APP amyloid precursor protein βCTF beta C-terminal fragment

MCI mild cognition impairment ROS reactive oxygen species LPS lipopolysaccharide

MAP microtubule-associated proteins

GSK3β glycogen synthase kinase-3 β

BACE aspartyl protease β-site APP-cleaving enzyme

ADAM disintegrin and metalloprotease domain

TGF-β transforming growth factor-beta

**Abbreviations**

mediators. In fact, it is related to a greater degree with the progression of the disease and worsening of the symptoms with the increase of phosphorylated TAU in different parts of the brain. In the last years, the therapies have been focused on elimination of the Aβ from the brain of the Alzheimer's patient with poor results [157]. In addition, reactive astrocytes greatly increase NRF-2, which is an antioxidant protein and could produce beneficial effects in Alzheimer's disease [157]. The regulation of oxidative stress or inflammation could help the conservation of neurons located near astrocytes and microglia. Future therapies should be aimed at the development of specific drugs that control the formation of reactive astrocytes and that favor the correct resolution of the inflammation produced by Alzheimer's disease. The study of the genetic mechanisms that predispose to increase amounts of hyperphosphorylated TAU or those that decrease phosphorylation of TAU would be interesting in order to understand cellular mechanisms implicated in AD [157]. Furthermore, the study of the main trigger of this basal chronic inflammation that worsens the clinical symptoms of AD patients, should be crucial to find new therapeutic strategies. Finally, regarding the relationship that exists between the astrocytes and the cells of the nervous system, there would be a greater study of the functions of these cells in the healthy individual. The control of the mechanisms and the understanding of the relationship between astrocytes with other neural cells could help, in the same way,

**96**

### **Author details**

Soraya L. Valles\*, Federico Burguet, Antonio Iradi, Martin Aldasoro, Jose M. Vila, Constanza Aldasoro and Adrián Jordá Department of Physiology, School of Medicine, University of Valencia, Spain

\*Address all correspondence to: lilian.valles@uv.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[126] Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG. Expression of beta amyloid protein precursor mRNAs: Recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron. 1990;**4**:253-267

[127] Peress NS, Perillo E. Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer's disease: A comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. Journal of Neuropathology and Experimental Neurology. 1995;**54**:802-811

[128] Wyss-Coray T, Borrow P, Brooker MJ, Mucke L. Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. Journal of Neuroimmunology. 1997;**77**:45-50

[129] Wyss-Coray T, Lin C, Yan F, Yu G-Q, Rohde M, McConlogue L, et al. TGF-b1 promotes microglial amyloid-b clearance and reduces plaque burden in transgenic mice. Nature Medicine. 2001;**7**:612-618

[130] LeBlanc AC, Papadopoulos M, Be'lair C, Chu W, Crosato M, Powell J, et al. Processing of amyloid precursor protein in human primary neuron and astrocyte cultures. Journal of Neurochemistry. 1997;**68**:1183-1190

[131] Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, Mariani J. Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proceedings of the National Academy of Sciences of the United States of America. 1995;**92**:3032-3035

[132] Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, et al. Interleukin 1 regulates synthesis of amyloid betaprotein precursor mRNA in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1989;**86**:7606-7610

[133] Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. The Biochemical Journal. 1990;**265**:621-636

[134] Raucher D. Tumor targeting peptides: Novel therapeutic strategies in glioblastoma. Current Opinion in Pharmacology. 2019;**47**:14-19

[135] Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012;**338**(6110):1080-1084

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[145] Huang J, Philbert MA. Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells. Brain Research.

[146] Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ, et al. Ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: Evidence that astrocytes play an important role in antioxidative processes in the brain. Journal of Neurochemistry.

[147] Lachapelle MY, Drouin G. Inactivation dates of the human and guinea pig vitamin C genes. Genetica.

[148] Covarrubias-Pinto A,

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[151] Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal

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1995;**680**:16-22

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2011;**139**:199-207

*DOI: http://dx.doi.org/10.5772/intechopen.88701*

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1996;**67**:2425-2433

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2010;**44**:479-496

2016;**595**:33-39

2009;**57**:244-257

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[139] Belanger M, Allaman I,

Magistretti PJ. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metabolism.

[140] Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Research.

[141] Gebicki JM. Oxidative stress, free radicals and protein peroxides. Archives

[142] Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA. Astrocytes protect neurons from nitric oxide toxicity by a glutathionedependent mechanism. Journal of Neurochemistry. 2001;**77**:1601-1610

[143] Fujita T, Tozaki-Saitoh H, Inoue K. P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal cultures. Glia.

Gutterer JM, Hirrlinger J, Hamprecht B. The glutathione system of peroxide detoxification is less efficient in

of Biochemistry and Biophysics.

*Astrocytes and Inflammatory Processes in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.88701*

culture is delayed by prenatal ethanol exposure. Journal of Neurochemistry. 1996;**67**:2425-2433

*Glia in Health and Disease*

[122] Shibata N, Ohnuma T, Takahashi T, Baba H, Ishizuka T, Ohtsuka M, et al. Effect of IL-6 polymorphism on risk of Alzheimer disease: Genotype–

[129] Wyss-Coray T, Lin C, Yan F, Yu G-Q, Rohde M, McConlogue L, et al. TGF-b1 promotes microglial amyloid-b clearance and reduces plaque burden in transgenic mice. Nature Medicine.

[130] LeBlanc AC, Papadopoulos M, Be'lair C, Chu W, Crosato M, Powell J, et al. Processing of amyloid precursor protein in human primary neuron and astrocyte cultures. Journal of Neurochemistry. 1997;**68**:1183-1190

[131] Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, Mariani J. Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proceedings of the National Academy of Sciences of the United States of America.

[132] Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, et al. Interleukin 1 regulates synthesis of amyloid betaprotein precursor mRNA in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America.

2001;**7**:612-618

1995;**92**:3032-3035

1989;**86**:7606-7610

[133] Heinrich PC, Castell JV,

Andus T. Interleukin-6 and the acute phase response. The Biochemical Journal. 1990;**265**:621-636

[134] Raucher D. Tumor targeting peptides: Novel therapeutic strategies in glioblastoma. Current Opinion in Pharmacology. 2019;**47**:14-19

[135] Friedmann-Morvinski D,

2012;**338**(6110):1080-1084

[136] Valles S, Sancho-Tello M,

Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science.

Miñana R, Climent E, Renau-Piqueras J, Guerri C. Glial fibrillary acidic protein expression in rat brain and in radial glia

phenotype association study in Japanese cases. American Journal of Medical

[123] Luedecking EK, DeKosky ST, Mehdi H, Ganguli M, Kamboh MI. Analysis of genetic polymorphisms

[124] Chao CC, Hu S, Frey WH, Ala TA, Tourtellotte WW, Peterson PK, et al. Transforming growth factor beta in Alzheimer's disease. Clinical and Diagnostic Laboratory Immunology.

[125] van der Wal EA, Go'mez-Pinilla F, Cotman CW. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport.

[126] Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG. Expression of beta amyloid protein precursor mRNAs: Recognition of a novel alternatively spliced form and quantitation in

Alzheimer's disease using PCR. Neuron.

[127] Peress NS, Perillo E. Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer's disease: A comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. Journal of Neuropathology and Experimental Neurology.

Genetics. 2002;**114**:436-439

in the transforming growth factorbeta1 gene and the risk of Alzheimer's disease. Human Genetics.

2000;**106**:565-569

1994;**1**:109-110

1993;**4**:69-72

1990;**4**:253-267

1995;**54**:802-811

[128] Wyss-Coray T, Borrow P, Brooker MJ, Mucke L. Astroglial

overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. Journal of Neuroimmunology. 1997;**77**:45-50

**106**

[137] Sancho-Tello M, Vallés S, Montoliu C, Renau-Piqueras J, Guerri C. Developmental pattern of GFAP and vimentin gene expression in rat brain and in radial glial cultures. Glia. 1995;**15**:157-166

[138] Kuramoto K, Yamamoto M, Suzuki S, Sanomachi T, Togashi K, Seino S, et al. AS602801, an anti-cancer stem cell drug candidate, suppresses gap-junction communication between lung cancer stem cells and astrocytes. Anticancer Research. 2018;**38**:5093-5099

[139] Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metabolism. 2011;**14**:724-738

[140] Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010;**44**:479-496

[141] Gebicki JM. Oxidative stress, free radicals and protein peroxides. Archives of Biochemistry and Biophysics. 2016;**595**:33-39

[142] Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA. Astrocytes protect neurons from nitric oxide toxicity by a glutathionedependent mechanism. Journal of Neurochemistry. 2001;**77**:1601-1610

[143] Fujita T, Tozaki-Saitoh H, Inoue K. P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal cultures. Glia. 2009;**57**:244-257

[144] Dringen R, Kussmaul L, Gutterer JM, Hirrlinger J, Hamprecht B. The glutathione system of peroxide detoxification is less efficient in

neurons than in astrocytes. Journal of Neurochemistry. 1999;**73**:S106-S106

[145] Huang J, Philbert MA. Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells. Brain Research. 1995;**680**:16-22

[146] Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ, et al. Ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: Evidence that astrocytes play an important role in antioxidative processes in the brain. Journal of Neurochemistry. 1994;**62**:45-53

[147] Lachapelle MY, Drouin G. Inactivation dates of the human and guinea pig vitamin C genes. Genetica. 2011;**139**:199-207

[148] Covarrubias-Pinto A, Acuña AI, Beltrán FA, Torres-Díaz L, Castro MA. Old things new view: Ascorbic acid protects the brain in neurodegenerative disorders. International Journal of Molecular Sciences. 2015;**16**(12):28194-28217

[149] Castro MA, Beltrán FA, Brauchi S, Concha II. A metabolic switch in brain: Glucose and lactate metabolism modulation by ascorbic acid. Journal of Neurochemistry. 2009;**110**(2):423-440

[150] Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer's disease: Why did antioxidant therapy fail? Oxidative Medicine and Cellular Longevity. 2014;**2014**:427318

[151] Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal

viability. The Journal of Neuroscience. 2010;**30**:3326-3338

[152] Haydon PG. Astrocytes and the modulation of sleep. Current Opinion in Neurobiology. 2017;**44**:28-33

[153] Delekate A, Fuchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nature Communications. 2014;**5**:5422

[154] Rossi D, Brambilla L, Valori CF, Crugnola A, Giaccone G, Capobianco R, et al. Defective tumornecrosis factoralpha-dependent control of astrocyte glutamate release in atransgenic mouse model of Alzheimer disease. The Journal of Biological Chemistry. 2005;**280**:42088-42096

[155] Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proceedings of the National Academy of Sciences of the United States of America. 2013;**110**:E2518-E2527

[156] Valles SL, Borrás C, Gambini J, Furriol J, Ortega A, Sastre J, et al. Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell. 2008;**7**:112-118

[157] Liu B, Teschemacher AG, Kasparov S. Neuroprotective potential of astroglia. Journal of Neuroscience Research. 2017;**95**:2126-2139

**109**

**Chapter 6**

**Abstract**

neuroinfectious diseases.

astrogliosis

**1. Introduction**

Astrocytes: Initiators of and

Responders to Inflammation

We are in the midst of a glial renaissance; astrocytes, essential for brain homeostasis and neuroprotection, have experienced resurgence in focused analyses. New roles in synaptic plasticity, innate immunity and control of recruited immune cells have placed astrocytes at the center of central nervous system functions. Astrocytes have been shown to receive and convey information to all neural cell types in a coordinated effort to respond to injury and infection, initiating reparative mechanisms. Astrocytes detect injury and infection signals from neurons, microglia, oligodendrocytes and endothelial cells, responding by secreting cytokines, chemokines and growth factors, which may activate immune defenses. While regional heterogeneity in astrocyte form and function has been appreciated since the early 1990s, technologic advances have allowed scientists to show only that astrocytes may be as individualized as neurons. Adult astrocytes may undergo a morphological and functional transformation referred to as astrogliosis. Newly generated astrocytes exhibit heterogenous phenotypes; thus, some remove toxic molecules, restore blood-brain barrier function, and promote extracellular matrix components to support axonal growth and repair, while others inhibit neuronal repair and regeneration. This chapter will introduce some of the cellular and molecular components involved in astrocyte responses induced by inflammatory mediators or pathogens during neuroinflammation or

**Keywords:** astrocyte, cytokines, chemokines, pathogens, viruses, bacteria,

Astrocytes are a principle participant in central nervous system (CNS) responses to neurological disorders or diseases [1–3]. During development and homeostasis, astrocytes coordinate immune responses by regulating microglia activation and blood-brain barrier (BBB) formation [4, 5]. Through dedicated molecular cascades, astrocytes also provide growth factors to neurons, support synapse formation, and help regulate extracellular balance of ions and neurotransmitters, making these glial cells essential for brain homeostasis [6, 7]. In response to CNS injury and disease, astrocytes undergo a process termed astrogliosis, a multifactorial and complex remodeling of astrocytes [7–10]. Despite the use of a single term to describe astrocyte reaction to insult, astrogliosis results in a spectrum of heterogenous changes in a context specific manner that vary with etiology and severity of

*Allison Soung and Robyn S. Klein*

### **Chapter 6**

*Glia in Health and Disease*

2010;**30**:3326-3338

viability. The Journal of Neuroscience.

[152] Haydon PG. Astrocytes and the modulation of sleep. Current Opinion in

Neurobiology. 2017;**44**:28-33

[153] Delekate A, Fuchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor

hyperactivity in vivo in an Alzheimer's

[154] Rossi D, Brambilla L, Valori CF, Crugnola A, Giaccone G, Capobianco R, et al. Defective tumornecrosis factoralpha-dependent control of astrocyte glutamate release in atransgenic mouse model of Alzheimer disease. The Journal of Biological Chemistry.

Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Proceedings of the National Academy of Sciences of the United States of America. 2013;**110**:E2518-E2527

[156] Valles SL, Borrás C, Gambini J, Furriol J, Ortega A, Sastre J, et al. Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell.

[157] Liu B, Teschemacher AG,

Research. 2017;**95**:2126-2139

Kasparov S. Neuroprotective potential of astroglia. Journal of Neuroscience

signalling mediates astrocytic

disease mouse model. Nature Communications. 2014;**5**:5422

2005;**280**:42088-42096

[155] Talantova M, Sanz-

2008;**7**:112-118

**108**

## Astrocytes: Initiators of and Responders to Inflammation

*Allison Soung and Robyn S. Klein*

### **Abstract**

We are in the midst of a glial renaissance; astrocytes, essential for brain homeostasis and neuroprotection, have experienced resurgence in focused analyses. New roles in synaptic plasticity, innate immunity and control of recruited immune cells have placed astrocytes at the center of central nervous system functions. Astrocytes have been shown to receive and convey information to all neural cell types in a coordinated effort to respond to injury and infection, initiating reparative mechanisms. Astrocytes detect injury and infection signals from neurons, microglia, oligodendrocytes and endothelial cells, responding by secreting cytokines, chemokines and growth factors, which may activate immune defenses. While regional heterogeneity in astrocyte form and function has been appreciated since the early 1990s, technologic advances have allowed scientists to show only that astrocytes may be as individualized as neurons. Adult astrocytes may undergo a morphological and functional transformation referred to as astrogliosis. Newly generated astrocytes exhibit heterogenous phenotypes; thus, some remove toxic molecules, restore blood-brain barrier function, and promote extracellular matrix components to support axonal growth and repair, while others inhibit neuronal repair and regeneration. This chapter will introduce some of the cellular and molecular components involved in astrocyte responses induced by inflammatory mediators or pathogens during neuroinflammation or neuroinfectious diseases.

**Keywords:** astrocyte, cytokines, chemokines, pathogens, viruses, bacteria, astrogliosis

### **1. Introduction**

Astrocytes are a principle participant in central nervous system (CNS) responses to neurological disorders or diseases [1–3]. During development and homeostasis, astrocytes coordinate immune responses by regulating microglia activation and blood-brain barrier (BBB) formation [4, 5]. Through dedicated molecular cascades, astrocytes also provide growth factors to neurons, support synapse formation, and help regulate extracellular balance of ions and neurotransmitters, making these glial cells essential for brain homeostasis [6, 7]. In response to CNS injury and disease, astrocytes undergo a process termed astrogliosis, a multifactorial and complex remodeling of astrocytes [7–10]. Despite the use of a single term to describe astrocyte reaction to insult, astrogliosis results in a spectrum of heterogenous changes in a context specific manner that vary with etiology and severity of

### **Figure 1.**

*Astrogliosis is typically characterized by hypertrophy of astrocyte processes. Expression of GFAP+ astrocytes (green) and DAPI (blue) in a mock-infected mouse CA3 hippocampus (A) and in a West Nile virus-infected CA3 hippocampus 7 days post infection (B). Viral infection triggers reactive astrogliosis in the hippocampus, in which the processes of activated astrocytes show hypertrophy.*

CNS injury [9–13]. Classically, this process is characterized by upregulation of glial fibrillary acid protein (GFAP) and vimentin, key astrocyte intermediate filaments, and hypertrophy of astrocyte processes [14] (**Figure 1**). Changes in astrocyte biochemistry and physiology that may result in the secretion of anti-inflammatory and pro-inflammatory factors also contribute to this process [10, 15–17].

### **2. Astrogliosis**

Functionally, astrogliosis results in the expression of molecules that provide neurotrophic support to injured neurons, isolate damaged area and CNS inflammation from healthy CNS tissue, rebuild and maintain a compromised BBB, and contribute circuitry remodeling around the lesioned region [7, 9–12, 18]. Consistent with this, studies using animal models of traumatic brain injury, spinal cord injury, and autoimmunity, all reveal that the loss of reactive astrocytes during acute processes leads to the exacerbation of clinical symptoms, recruit of immune molecules, changes in BBB integrity, and neuronal death [7, 10, 19]. The overall goals of these functional reactions are therefore beneficial for the CNS. However, past research has also highlighted detrimental and inhibitory effects of astrogliosis, including augmentation of inflammation, as well as inhibition of neuronal repair and axonal growth [20, 21]. The dual outcomes of astrogliosis highlight the time- and context-specific way this process may be regulated. Future studies of this process may ultimately determine mechanisms to manipulate astrogliosis as a therapeutic target to improve CNS injury outcomes [10, 22].

Astrogliosis is induced and regulated by a variety of extracellular molecules, such as neurotransmitters, steroid hormones, cytokines and neurodegenerationassociated molecules (**Table 1**). Intracellular signaling pathways, such cyclic AMP (cAMP), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NFκB), Rho-kinase, and calcium have all been observed to induce the expression of GFAP or vimentin [11, 45–47]. Extracellular signaling pathways, including responses to epidermal growth factor (EGF), fibroblast growth factor

**111**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

> **Injury Chemokines/cytokines released**

ERα signaling EAE Reduction of

EAE Downregulation of IL-17 and IFNγ

IL-17 signaling EAE Upregulation of CXCL2 Increase of leukocyte

CCL5, IL-1β and TNF

CCL2, CCL5, CXCL10, IL-1β, IFNγ, and TNF; downregulation of IL-6

Upregulation of CCL2, CCL5, CXCL10, IL-6, TGF-β and TNF

SHH signaling EAE Maintenance of BBB [36]

Notch signaling Ischemia Reduction of

EAE Increases of T cell

Infection Downregulation of IFNγ Inhibition of

**Immune/functional** 

leukocyte molecules

astrocyte apoptosis, decrease of pathogen

Increase of GFAP expression

infiltration, worsen disease course

Improved course of

Increase of GFAP expression

infiltration, worsen disease course

Reduction of leukocyte molecules, increase in axon pathology, worsen disease course

Increase of leukocytes molecules, reduction of GFAP expression, increase of neuronal

damage

leukocyte molecules, increase of GFAP expression, increase of astrocyte proliferation

Increase of leukocyte molecules, increase of GFAP expression

Increase of GFAP and vimentin expression

Reduction of leukocyte molecules, inhibition of GFAP expression

burden

disease

Reduction of T cell infiltration, inhibition of astrocyte apoptosis, improvement of disease course

**References**

[23]

[25]

[26, 27]

[28]

[24]

[29]

[30]

[31]

[31–33]

[34, 35]

[37]

[37, 38]

[39, 40]

[24, 25]

**outcome**

**Signaling pathway**

Gp103/IL-6 signaling

TNFR1 signaling

IL-1β signaling Traumatic

injury, infection

IFNγ signaling EAE Downregulation of

Traumatic injury

NFκB signaling EAE Upregulation of

Ischemia, traumatic injury

Soc3 signaling Traumatic

STAT3 signaling Traumatic

injury

injury

Traumatic injury


*Glia in Health and Disease*

**2. Astrogliosis**

**Figure 1.**

CNS injury [9–13]. Classically, this process is characterized by upregulation of glial fibrillary acid protein (GFAP) and vimentin, key astrocyte intermediate filaments, and hypertrophy of astrocyte processes [14] (**Figure 1**). Changes in astrocyte biochemistry and physiology that may result in the secretion of anti-inflammatory

*Astrogliosis is typically characterized by hypertrophy of astrocyte processes. Expression of GFAP+ astrocytes (green) and DAPI (blue) in a mock-infected mouse CA3 hippocampus (A) and in a West Nile virus-infected CA3 hippocampus 7 days post infection (B). Viral infection triggers reactive astrogliosis in the hippocampus, in* 

Functionally, astrogliosis results in the expression of molecules that provide neurotrophic support to injured neurons, isolate damaged area and CNS inflammation from healthy CNS tissue, rebuild and maintain a compromised BBB, and contribute circuitry remodeling around the lesioned region [7, 9–12, 18]. Consistent with this, studies using animal models of traumatic brain injury, spinal cord injury, and autoimmunity, all reveal that the loss of reactive astrocytes during acute processes leads to the exacerbation of clinical symptoms, recruit of immune molecules, changes in BBB integrity, and neuronal death [7, 10, 19]. The overall goals of these functional reactions are therefore beneficial for the CNS. However, past research has also highlighted detrimental and inhibitory effects of astrogliosis, including augmentation of inflammation, as well as inhibition of neuronal repair and axonal growth [20, 21]. The dual outcomes of astrogliosis highlight the time- and context-specific way this process may be regulated. Future studies of this process may ultimately determine mechanisms to manipulate astrogliosis as a therapeutic target to improve CNS injury outcomes

Astrogliosis is induced and regulated by a variety of extracellular molecules, such as neurotransmitters, steroid hormones, cytokines and neurodegenerationassociated molecules (**Table 1**). Intracellular signaling pathways, such cyclic AMP (cAMP), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NFκB), Rho-kinase, and calcium have all been observed to induce the expression of GFAP or vimentin [11, 45–47]. Extracellular signaling pathways, including responses to epidermal growth factor (EGF), fibroblast growth factor

and pro-inflammatory factors also contribute to this process [10, 15–17].

*which the processes of activated astrocytes show hypertrophy.*

**110**

[10, 22].


*A variety of intracellular signaling molecules have been shown to induce reactive astrogliosis or to modulate aspects of the reactive astrogliosis process. In response to a range of CNS injuries, all cell types within the CNS, such as neurons, microglia, other astrocytes, endothelium, and pericytes, can release signaling molecules that are able to trigger astrogliosis.*

*BBB = blood-brain barrier, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, ER = estrogen receptor, Gp = glycoprotein, IL = interleukin, IFN = interferon, NFκB = nuclear factor kappa B, EAE = experimental autoimmune encephalomyelitis, ECM = extracellular matrix, SHH = sonic hedgehog, Soc3 = suppressor of cytokine signaling 3, STAT3 = signaling transducer and activator of transcription 3, TGF = transforming growth factor β, TNF = tumor necrosis factor.*

### **Table 1.**

*Triggers of reactive astrogliosis.*

(FGF), sonic hedgehog (SHH), and albumin, can also regulate astrocyte proliferation [9, 48–50]. Specific pro- and anti-inflammatory effects of reactive astrocytes may be regulated separately. Thus, the genetic ablation of STAT3 within astrocytes, or its associated membrane receptor gp130, leads to increased inflammation during autoimmune disease, traumatic injury and infection [24, 37–39, 51], while genetic deletion of NFκB or the suppressor of cytokine signaling 3 (Soc3) signaling pathway in astrocytes decreases the recruitment of immune cells [31, 32, 37]. Furthermore, recruited immune cells release numerous cytokines that may further stimulate astrocyte activation (**Table 1**). In addition, recent studies indicate that microglia critically induce astrogliosis via expression of pro-inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor (TNF), and interferon (IFN)-γ [26, 52, 53].

In response to injury, reactive astrocytes were previously believed to migrate to the lesion site. Recent live imaging studies, however, indicate that astrocytes do not migrate towards the lesion site [54]. Instead, astrocytes remain in their tileddomains and become hypertrophic [54, 55]. Neither proliferation nor migration of astrocytes contribute to the total increase of GFAP positive cells observed at lesion sites. This has led to a new focus on identifying other sources for adult astrocytes. Currently, there is evidence that radial glia, neuronal progenitor cells (NPCs) within the subventricular (SVZ) and subgranular (SGZ) zones, locally proliferating glia, in addition to NG2+ cells may all contribute to newly generated pools of reactive astrocytes after injury [56].

### **3. Astrocytes as the gatekeeper to the CNS**

During homeostasis, astrocyte end-feet enwrap the brain microvascular endothelial cells, helping maintain the integrity of the BBB. Their physical interaction with the BBB allows astrocytes to influence the entry of peripheral immune cells into the CNS during injury or disease as well as modulating their activity once entering the CNS parenchyma. In health, astrocytes, along with multiple other cell types, support the BBB as well as express localizing cues that restrict leukocytes

**113**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

**4. Reactive astrocytes as a physical barrier**

immune cells [24, 25, 38, 39, 60–66].

tion model [77].

access into the CNS parenchyma [17, 57–59]. However, CNS damage caused by stroke, traumatic injury, infection, autoimmune disease, and neurodegenerative disorders leads to the disruption of the BBB, which may increase the CNS entry of

During injury or infection, astrocytes detect molecular changes in their extracellular environment and in neighboring cells. In stroke, astrocytes become reactive when oxygen and glucose deprivation occurs [67, 68]. In most neurological disorders, the release of neurotransmitters and adenosine triphosphate (ATP) from damaged neurons is detected by astrocytes via P2X and P2Y purinergic receptors [69, 70]. During viral infections, toll-like receptors (TLRs), such as TLR3, 7, and 9, and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), are expressed on neurons, astrocytes, and microglia. These receptors are examples of pattern recognition receptors (PPRs) that are differentially activated by pathogen-associated molecular patterns (PAMPs) derived from invading bacteria, fungi, or viruses [71]. Activation of TLRs and RLRs by PAMPs or damage-associated molecular patterns (DAMPs) have been shown to contribute to neuronal damage, induce microglia and astrocyte activation and production of cytokines, including type I IFNs [72–74]. Type I IFNs, along with numerous other innate cytokines, such as IL-6, IL-1β, IFN-γ, and TNF, have been shown to regulate BBB integrity through a variety of different mechanisms that include the regulation of Rho GTPases, activation of matrix metallopeptidase 9 (MMP9), and suppression of other pro-inflammatory cytokines, including IL-1β, IL-6, and TNF [75, 76]. In support of this, the genetic astrocyte-specific deletion of the type I IFN receptor, IFNαβR (IFNAR), results in enhanced BBB permeability in a murine viral infec-

The entry of leukocytes into the CNS parenchyma involves their passage across the BBB, whose permeability is regulated by astrocytes and pericytes, as well as multiple other cell types [57–59]. Once leukocytes traverse the BBB, they localize within perivascular spaces and where they interact with numerous cell types, including astrocytes [78]. Astrocytes, thus, take part in both the recruitment and restriction of leukocytes in the CNS [58, 59, 151]. Their functions, however, occur in a context-specific manner via specific signaling events. It is remarkable how astrocytes are able to respond to a diverse number of signaling mechanisms in the orchestration BBB disruption, the recruitment of leukocytes, and the amplification of their pro-inflammatory effects [17, 57, 79, 80], while also being capable of contributing to BBB repair, restricting leukocyte trafficking, and exerting antiinflammatory effects that promote the resolution of inflammation [6, 9–11].

At the site of injury, newly proliferated astrocytes form scars, in which bundles of reactive astrocytes polarize with extracellular matrix (ECM) components and physically surround the lesioned site [38]. The earliest studies focused on the formation of the astrocyte scar and its importance in repairing the BBB after traumatic brain injury [61, 62]. Astrocyte scars form a physical, functional barrier that restricts the entry of leukocytes after traumatic brain injuries, ischemia, neurodegeneration and autoimmune inflammation [37, 38]. This is achieved through the upregulation of ECM proteins, such as fibronectin and laminin, as well as chondroitin sulfate proteoglycans (CSPGs) [41, 42, 81–84]. Structural proteins, such as GFAP and vimentin, have also been shown to be important for the formation of the astrocyte scar [14]. Mice with global genetic

*Glia in Health and Disease*

TGF-β signaling Traumatic

injury

*TGF = transforming growth factor β, TNF = tumor necrosis factor.*

**Signaling pathway**

*trigger astrogliosis.*

*Triggers of reactive astrogliosis.*

**Table 1.**

(IFN)-γ [26, 52, 53].

tive astrocytes after injury [56].

**3. Astrocytes as the gatekeeper to the CNS**

(FGF), sonic hedgehog (SHH), and albumin, can also regulate astrocyte proliferation [9, 48–50]. Specific pro- and anti-inflammatory effects of reactive astrocytes may be regulated separately. Thus, the genetic ablation of STAT3 within astrocytes, or its associated membrane receptor gp130, leads to increased inflammation during autoimmune disease, traumatic injury and infection [24, 37–39, 51], while genetic deletion of NFκB or the suppressor of cytokine signaling 3 (Soc3) signaling pathway in astrocytes decreases the recruitment of immune cells [31, 32, 37]. Furthermore, recruited immune cells release numerous cytokines that may further stimulate astrocyte activation (**Table 1**). In addition, recent studies indicate that microglia critically induce astrogliosis via expression of pro-inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor (TNF), and interferon

**Injury Chemokines/cytokines released**

> NFκB signaling; downregulation of CCL5

*BBB = blood-brain barrier, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, ER = estrogen receptor, Gp = glycoprotein, IL = interleukin, IFN = interferon, NFκB = nuclear factor kappa B, EAE = experimental autoimmune encephalomyelitis, ECM = extracellular matrix, SHH = sonic hedgehog, Soc3 = suppressor of cytokine signaling 3, STAT3 = signaling transducer and activator of transcription 3,* 

*A variety of intracellular signaling molecules have been shown to induce reactive astrogliosis or to modulate aspects of the reactive astrogliosis process. In response to a range of CNS injuries, all cell types within the CNS, such as neurons, microglia, other astrocytes, endothelium, and pericytes, can release signaling molecules that are able to* 

Infection Inhibition of

**Immune/functional** 

Increase of leukocyte molecules, increase of GFAP expression, increase of ECM components

Reduction of T cell infiltration, decrease of neuronal death

**References**

[41–43]

[44]

**outcome**

In response to injury, reactive astrocytes were previously believed to migrate to the lesion site. Recent live imaging studies, however, indicate that astrocytes do not migrate towards the lesion site [54]. Instead, astrocytes remain in their tileddomains and become hypertrophic [54, 55]. Neither proliferation nor migration of astrocytes contribute to the total increase of GFAP positive cells observed at lesion sites. This has led to a new focus on identifying other sources for adult astrocytes. Currently, there is evidence that radial glia, neuronal progenitor cells (NPCs) within the subventricular (SVZ) and subgranular (SGZ) zones, locally proliferating glia, in addition to NG2+ cells may all contribute to newly generated pools of reac-

During homeostasis, astrocyte end-feet enwrap the brain microvascular endothelial cells, helping maintain the integrity of the BBB. Their physical interaction with the BBB allows astrocytes to influence the entry of peripheral immune cells into the CNS during injury or disease as well as modulating their activity once entering the CNS parenchyma. In health, astrocytes, along with multiple other cell types, support the BBB as well as express localizing cues that restrict leukocytes

**112**

access into the CNS parenchyma [17, 57–59]. However, CNS damage caused by stroke, traumatic injury, infection, autoimmune disease, and neurodegenerative disorders leads to the disruption of the BBB, which may increase the CNS entry of immune cells [24, 25, 38, 39, 60–66].

During injury or infection, astrocytes detect molecular changes in their extracellular environment and in neighboring cells. In stroke, astrocytes become reactive when oxygen and glucose deprivation occurs [67, 68]. In most neurological disorders, the release of neurotransmitters and adenosine triphosphate (ATP) from damaged neurons is detected by astrocytes via P2X and P2Y purinergic receptors [69, 70]. During viral infections, toll-like receptors (TLRs), such as TLR3, 7, and 9, and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), are expressed on neurons, astrocytes, and microglia. These receptors are examples of pattern recognition receptors (PPRs) that are differentially activated by pathogen-associated molecular patterns (PAMPs) derived from invading bacteria, fungi, or viruses [71]. Activation of TLRs and RLRs by PAMPs or damage-associated molecular patterns (DAMPs) have been shown to contribute to neuronal damage, induce microglia and astrocyte activation and production of cytokines, including type I IFNs [72–74]. Type I IFNs, along with numerous other innate cytokines, such as IL-6, IL-1β, IFN-γ, and TNF, have been shown to regulate BBB integrity through a variety of different mechanisms that include the regulation of Rho GTPases, activation of matrix metallopeptidase 9 (MMP9), and suppression of other pro-inflammatory cytokines, including IL-1β, IL-6, and TNF [75, 76]. In support of this, the genetic astrocyte-specific deletion of the type I IFN receptor, IFNαβR (IFNAR), results in enhanced BBB permeability in a murine viral infection model [77].

The entry of leukocytes into the CNS parenchyma involves their passage across the BBB, whose permeability is regulated by astrocytes and pericytes, as well as multiple other cell types [57–59]. Once leukocytes traverse the BBB, they localize within perivascular spaces and where they interact with numerous cell types, including astrocytes [78]. Astrocytes, thus, take part in both the recruitment and restriction of leukocytes in the CNS [58, 59, 151]. Their functions, however, occur in a context-specific manner via specific signaling events. It is remarkable how astrocytes are able to respond to a diverse number of signaling mechanisms in the orchestration BBB disruption, the recruitment of leukocytes, and the amplification of their pro-inflammatory effects [17, 57, 79, 80], while also being capable of contributing to BBB repair, restricting leukocyte trafficking, and exerting antiinflammatory effects that promote the resolution of inflammation [6, 9–11].

### **4. Reactive astrocytes as a physical barrier**

At the site of injury, newly proliferated astrocytes form scars, in which bundles of reactive astrocytes polarize with extracellular matrix (ECM) components and physically surround the lesioned site [38]. The earliest studies focused on the formation of the astrocyte scar and its importance in repairing the BBB after traumatic brain injury [61, 62]. Astrocyte scars form a physical, functional barrier that restricts the entry of leukocytes after traumatic brain injuries, ischemia, neurodegeneration and autoimmune inflammation [37, 38]. This is achieved through the upregulation of ECM proteins, such as fibronectin and laminin, as well as chondroitin sulfate proteoglycans (CSPGs) [41, 42, 81–84]. Structural proteins, such as GFAP and vimentin, have also been shown to be important for the formation of the astrocyte scar [14]. Mice with global genetic

deletion of these molecules display increased inflammation and pathology as well as worsened functional outcomes in various CNS injury models, such as ischemia, traumatic injury, autoimmune inflammation, infection, and neurodegeneration [11, 63, 64, 85–88].

The astrocyte scar is also important for localizing immune cells and limiting the invasion of infectious pathogens, to the lesion site. For example, the genetic deletion of GFAP+ cells leads to increases in immune cell infiltrations in murine models of traumatic injury and autoimmunity [60, 61]. Genetic loss of GFAP expression also increases pathogen burden in various infections, including *Staphylococcus aureus* and *Toxoplasma gondii* [89]. Multiple studies have shown that the restriction of leukocyte entry and migration after infection, autoimmune inflammation, and traumatic brain injury is mediated by astrocyte anti-inflammatory functions via the JAK2-STAT3 signaling pathway in GFAP+ cells [25, 38, 39]. The genetic deletion of astrocyte derived STAT3 signaling prevents scar formation and limits immune cell infiltration in a spinal cord injury model [39]. These observations suggest that the astrocyte scar serves as a functional barrier to restrict cytotoxic inflammatory molecules and cells.

Studies genetically deleting essential components of the ECM, such as MMP9, or inhibiting signaling pathways, including Rho/ROCK, to block CSPG activity have shown astrogliosis to exacerbate inflammation after traumatic injury or autoimmune inflammation as well as preventing axonal growth and behavioral recovery [81, 90–92]. The astrocyte scar has also been shown to exhibit a diverse array of molecules known to prevent axonal growth, such as CSPGs, semaphoring 3A, keratan sulfate proteoglycans (KSPGs) and ephrins/Eph receptors [19, 93, 94]. The complexity of astrocytes in producing, recruiting and restricting inflammatory cells and other molecules have made these cells a difficult target for potential therapeutic manipulation.

### **5. Astrocytes as a regulator of the innate immune response**

After CNS injury or infection, reactive astrocytes release molecules that attract, recruit and facilitate the migration of immune cells to the lesion site (**Figure 2**). Astrocytes express leukocyte adhesion molecules, including vascular cell adhesion and intercellular adhesion molecules, in models of ischemia, autoimmunity, and infection [30, 33, 95]. Specifically, in an ischemia model, astrocytes release NF-κB, which increases both vascular cell adhesion and intercellular adhesion molecules [33, 96]. These adhesion molecules promote intercellular interactions that contribute to the trafficking of immune cells to the lesion site.

Like microglia, the resident macrophages of the CNS, astrocytes play a role in innate immune responses by producing cytokines and chemokines, such as type I and II IFNs and TNF, that promote the expression of hundreds of interferonstimulated genes (ISGs), such as those that participate in inflammatory cell infiltration [97, 98]. Microglia also upregulate the expression of numerous receptors and produce various chemokines after CNS injury, such as chemokine (C-X3-C motif) receptor 1 (CX3CR1) and chemokine (C-C motif) receptor 2 (CCR2) [99]. Similarly, reactive astrocytes also express many of these receptors and chemokines, suggesting that astrocytes and microglia communicate via chemokines. In fact, astrocyte release of chemokines has been shown to be important for attracting peripheral and CNS myeloid cells to the lesion site. In models of traumatic injury and parasitic infection, astrocytes are a source of chemokine (C-C motif) ligand 2 (CCL2) [100, 101]. Astrocytes have also been shown to produce chemokine

**115**

[102–104].

**Figure 2.**

responses may be context dependent.

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

(C-X3-C motif) ligand 1 (CXC3L1) and CXCL1, detected by monocytes and microglia, in response to viral infection and spinal cord injury, respectively

*PRR = pattern recognition receptor, TNF = tumor necrosis factor.*

*Reactive astrocytes regulate immune responses. Activation of astrocytes, either directly by purinergic receptors or PRRs or indirectly, promote expression of inflammatory cytokines and chemokines as well as growth factors. The astrocyte response to molecular changes in their microenvironment shapes the recruitment and activation of peripheral immune cells, modulation of the BBB, and cell-cell interaction (not shown). ATP = adenosine triphosphate, BAFF = B-cell activating factor, BBB = blood-brain barrier, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, DAMPs = damage-associated molecular pattern, IL = interleukin, IFN = interferon, PAMP = pathogen-associated molecular pattern,* 

**6. Astrocytes as a regulator of the adaptive immune response**

During the adaptive immune response, astrocytes are a major source of T and B cells chemoattractants. Reactive astrocytes express CCL5 as well as CXCL10 in infection models, both chemoattractants of T cells [111–113]. In viral infection models, CXCL10 has been shown to be an important ligand for CXCR3 on CD8+ T cells [114]. The recruitment of such CXCR3+ T cells results in improved viral control and survival after infection [115]. In brain samples from patients with multiple

After entry into the brain, or activation within the brain, innate immune cells demonstrate a spectrum of phenotypes, ranging from pro- and anti-inflammatory states, and can express a variety of cytokines and chemokines, including IL-1β, IFN-γ, and TNF, that contribute to neuroinflammation [105]. Reactive astrocytes have a demonstrated role in modulating immune responses by releasing cytokines that stimulate microglia and macrophages to adopt either pro- or anti-inflammatory responses. For example, after injury or infection, astrocytes have been shown to release cytokines, such as IFN-γ, TNF, and IL-12, that shift microglia and macrophages to a more pro-inflammatory phenotype [106, 107]. Under similar conditions, however, astrocytes have also been observed to produced cytokines, including IL-10 and transforming growth factor beta (TGF-β), which can shift monocytes towards a less inflammatory states [108–110]. These findings support the notion that astrocyte *Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

### **Figure 2.**

*Glia in Health and Disease*

molecules and cells.

manipulation.

generation [11, 63, 64, 85–88].

deletion of these molecules display increased inflammation and pathology as well as worsened functional outcomes in various CNS injury models, such as ischemia, traumatic injury, autoimmune inflammation, infection, and neurode-

The astrocyte scar is also important for localizing immune cells and limiting the invasion of infectious pathogens, to the lesion site. For example, the genetic deletion of GFAP+ cells leads to increases in immune cell infiltrations in murine models of traumatic injury and autoimmunity [60, 61]. Genetic loss of GFAP expression also increases pathogen burden in various infections, including *Staphylococcus aureus* and *Toxoplasma gondii* [89]. Multiple studies have shown that the restriction of leukocyte entry and migration after infection, autoimmune inflammation, and traumatic brain injury is mediated by astrocyte anti-inflammatory functions via the JAK2-STAT3 signaling pathway in GFAP+ cells [25, 38, 39]. The genetic deletion of astrocyte derived STAT3 signaling prevents scar formation and limits immune cell infiltration in a spinal cord injury model [39]. These observations suggest that the astrocyte scar serves as a functional barrier to restrict cytotoxic inflammatory

Studies genetically deleting essential components of the ECM, such as MMP9, or inhibiting signaling pathways, including Rho/ROCK, to block CSPG activity have shown astrogliosis to exacerbate inflammation after traumatic injury or autoimmune inflammation as well as preventing axonal growth and behavioral recovery [81, 90–92]. The astrocyte scar has also been shown to exhibit a diverse array of molecules known to prevent axonal growth, such as CSPGs, semaphoring 3A, keratan sulfate proteoglycans (KSPGs) and ephrins/Eph receptors [19, 93, 94]. The complexity of astrocytes in producing, recruiting and restricting inflammatory cells and other molecules have made these cells a difficult target for potential therapeutic

After CNS injury or infection, reactive astrocytes release molecules that attract, recruit and facilitate the migration of immune cells to the lesion site (**Figure 2**). Astrocytes express leukocyte adhesion molecules, including vascular cell adhesion and intercellular adhesion molecules, in models of ischemia, autoimmunity, and infection [30, 33, 95]. Specifically, in an ischemia model, astrocytes release NF-κB, which increases both vascular cell adhesion and intercellular adhesion molecules [33, 96]. These adhesion molecules promote intercellular interactions that contrib-

Like microglia, the resident macrophages of the CNS, astrocytes play a role in innate immune responses by producing cytokines and chemokines, such as type I and II IFNs and TNF, that promote the expression of hundreds of interferonstimulated genes (ISGs), such as those that participate in inflammatory cell infiltration [97, 98]. Microglia also upregulate the expression of numerous receptors and produce various chemokines after CNS injury, such as chemokine (C-X3-C motif) receptor 1 (CX3CR1) and chemokine (C-C motif) receptor 2 (CCR2) [99]. Similarly, reactive astrocytes also express many of these receptors and chemokines, suggesting that astrocytes and microglia communicate via chemokines. In fact, astrocyte release of chemokines has been shown to be important for attracting peripheral and CNS myeloid cells to the lesion site. In models of traumatic injury and parasitic infection, astrocytes are a source of chemokine (C-C motif) ligand 2 (CCL2) [100, 101]. Astrocytes have also been shown to produce chemokine

**5. Astrocytes as a regulator of the innate immune response**

ute to the trafficking of immune cells to the lesion site.

**114**

*Reactive astrocytes regulate immune responses. Activation of astrocytes, either directly by purinergic receptors or PRRs or indirectly, promote expression of inflammatory cytokines and chemokines as well as growth factors. The astrocyte response to molecular changes in their microenvironment shapes the recruitment and activation of peripheral immune cells, modulation of the BBB, and cell-cell interaction (not shown). ATP = adenosine triphosphate, BAFF = B-cell activating factor, BBB = blood-brain barrier, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, DAMPs = damage-associated molecular pattern, IL = interleukin, IFN = interferon, PAMP = pathogen-associated molecular pattern, PRR = pattern recognition receptor, TNF = tumor necrosis factor.*

(C-X3-C motif) ligand 1 (CXC3L1) and CXCL1, detected by monocytes and microglia, in response to viral infection and spinal cord injury, respectively [102–104].

After entry into the brain, or activation within the brain, innate immune cells demonstrate a spectrum of phenotypes, ranging from pro- and anti-inflammatory states, and can express a variety of cytokines and chemokines, including IL-1β, IFN-γ, and TNF, that contribute to neuroinflammation [105]. Reactive astrocytes have a demonstrated role in modulating immune responses by releasing cytokines that stimulate microglia and macrophages to adopt either pro- or anti-inflammatory responses. For example, after injury or infection, astrocytes have been shown to release cytokines, such as IFN-γ, TNF, and IL-12, that shift microglia and macrophages to a more pro-inflammatory phenotype [106, 107]. Under similar conditions, however, astrocytes have also been observed to produced cytokines, including IL-10 and transforming growth factor beta (TGF-β), which can shift monocytes towards a less inflammatory states [108–110]. These findings support the notion that astrocyte responses may be context dependent.

### **6. Astrocytes as a regulator of the adaptive immune response**

During the adaptive immune response, astrocytes are a major source of T and B cells chemoattractants. Reactive astrocytes express CCL5 as well as CXCL10 in infection models, both chemoattractants of T cells [111–113]. In viral infection models, CXCL10 has been shown to be an important ligand for CXCR3 on CD8+ T cells [114]. The recruitment of such CXCR3+ T cells results in improved viral control and survival after infection [115]. In brain samples from patients with multiple sclerosis, astrocytes have been shown to express CXCL12, a T cell chemoattractant, and B-cell activating factor (BAFF), a B cell chemoattractant [116, 117]. Like their influence on microglia and macrophages, cytokines released by reactive astrocytes can shift T cells to adopt either a more beneficial or detrimental phenotype. For example, reactive astrocytes during autoimmunity release pro-inflammatory cytokines, including TNF, IFN-γ, and IL-17, which may induce T cells to adopt a more pro-inflammatory state. However, astrocytes have also been shown to release IL-10 that shifts T cells towards the anti-inflammatory spectrum [23, 24, 32, 118, 119]. Similarly, in a murine spinal cord injury model reactive astrocytes have been shown to release anti-inflammatory TGF-β [31]. Further studies examining the influences of reactive astrocytes on T cells are needed to better understand the long-term effects of astrogliosis on adaptive immune cells during CNS recovery after injury.

### **7. Reactive astrocytes as a pro-inflammatory regulator**

Reactive astrocytes can release a variety of molecular signals that contribute to the inflammatory state of the CNS after injury or disease by directly activating immune defenses with the release of cytokines, chemokines, and other growth factors (**Table 2**). Recent advancements in astrocyte transcriptome analysis have begun to reveal the context specific production of pro-inflammatory molecules by astrocytes as well as molecular triggers that induce their production. Analysis of the astrocyte transcriptome after *in vivo* exposure to lipopolysaccharide (LPS) or infection significantly promoted the production of a pro-inflammatory, neurotoxic molecular profile [26, 52]. However, the astrocyte transcriptome shifts towards an anti-inflammatory, neuroprotective profile in an *in vivo* ischemia model [52]. Future studies should utilize single-cell sequencing techniques to transcriptionally define individual astrocyte responses during health and disease.

Despite the number of astrocyte transcriptome data available, few studies have attempted to elucidate mechanisms and signaling cascades that mediate astrocyte pro-inflammatory production. Recent studies have indicated NFκB and SOC3 as transcriptional regulators of pro-inflammatory astrocytes after a traumatic brain injury and during autoimmune inflammation [31, 32, 37]. In a model of autoimmunity, genetic deletion of astrocyte derived NFκB results in increased expression of ECM components and pro-inflammatory cytokines [129]. Astrocytes have also been shown to release CCL2 and CXCL10 to recruit perivascular leukocytes during autoimmune inflammation [124–126]. While the role of CCL2 and CXCL10 is diverse, evidence suggests that these molecules produced by astrocytes promote leukocyte migration in the CNS parenchyma [124]. In an autoimmune inflammation model, IL-17 inflammatory induction has been shown to be mediated by astrocyte Act1 signaling. Genetically deleting Act1/IL-17 signaling from astrocytes in an EAE model prevents the induction of pro-inflammatory cytokines [28]. Reactive astrocytes can also shift towards a more pro-inflammatory state by overexpressing pro-inflammatory cytokines. In spinal cord injury and autoimmune models, the overexpression of IL-6 in astrocytes leads to increased immune cell infiltration. The proinflammatory cytokine, IL-1β, produced by astrocytes, has also been shown to initiate a signaling cascade that releases vasoactive endothelial growth factor (VEGF), leading to increased BBB permeability and leukocyte leakage [127, 128]. In general, there is also evidence that astrocytes contribute to triggering inflammatory responses due to increases in neuronal activity in epilepsy, neuropathic pain, and stress [130].

**117**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

**molecule**

Cytokines IL-6 and IL-10 Activation of numerous anti-

Growth factors TGF-β Activation of numerous anti-

Receptors ERα and Gp130 Suppression of multiple pro-

CXCL1, CXCL10, and CXCL12

Growth factors VEGF Increase of BBB permeability,

and TNF

*can shift reactive astrocytes to either a more beneficial or detrimental phenotype.*

**Immune outcome References**

Increase recruitment of leukocytes [95, 120, 122,

[95, 120]

[121, 122]

[36, 123]

[37–39]

[23, 25]

124, 125]

[95, 120–122]

[127, 128]

[31, 32, 37]

[28]

126]

inflammatory signaling pathways

inflammatory signaling pathways

inflammatory signaling pathways

inflammatory signaling pathways

Activation of numerous proinflammatory signaling pathways

increase of leukocyte infiltration

inflammatory signaling pathways

inflammatory signaling pathways

astrocyte proliferation

SHH Maintenance of BBB, increase of

STAT3 Suppression of multiple pro-

Chemokines CCL2 and CCL5 Increase recruitment of leukocytes [95, 120, 122,

NFκB and Soc3 Activation of numerous pro-

*As immune-competent cells, astrocytes can detect injury signals and respond with the release of cytokine, chemokines, and growth factors as well initiating intracellular signaling pathways. Data suggests that the downstream effects of astrocyte activation is context- and time-dependent, and that both factors as well as other microenvironment stimuli* 

*Act = actin, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, Gp = glycoprotein, IL = interleukin, IFN = interferon, NFκB = nuclear factor kappa B, EAE = experimental autoimmune encephalomyelitis, SHH = sonic hedgehog, Soc3 = suppressor of cytokine signaling 3, STAT3 = signaling transducer and activator of transcription 3, TGF = transforming growth factor β, TNF = tumor necrosis factor,* 

Act1 Activation of IL-17-mediated pro-

**Type Astrocyte** 

*Anti-inflammatory function*

Intracellular signaling

*Pro-inflammatory function*

Intracellular signaling

*VEGF = vascular endothelial growth factor.*

*Pro- and anti-immune responses of astrocyte molecules.*

molecules

**Table 2.**

Cytokines IL-6, IL-17, IL-1β,

molecules

**8. Reactive astrocytes as an anti-inflammatory regulator**

Despite the growing body of work that suggests pro-inflammatory roles for astrocytes, there is an equal amount of evidence suggesting these cells limit inflammation. Recent loss-of-function experiments have also revealed essential anti-inflammatory roles of astrocytes after a variety of CNS injury and disease states (**Table 2**). These studies have also revealed specific molecular mechanisms that mediate these anti-inflammatory roles. The astrocyte TGF-β response seems to selectively affect astrocyte cytokine and chemokine production after ischemia in murine models. The genetic deletion of TGF-β signaling in astrocytes leads to diffused inflammation and enhances myeloid cell activation [43, 44]. After toxoplasmic encephalitis, the genetic loss of astrocyte TGF-β signaling can lead to the increase of infiltrating T cells. Notably, in both examples, astrocyte TGF-β signaling controls infiltration immune cell number but not necessarily

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

*Glia in Health and Disease*

after injury.

disease.

sclerosis, astrocytes have been shown to express CXCL12, a T cell chemoattractant, and B-cell activating factor (BAFF), a B cell chemoattractant [116, 117]. Like their influence on microglia and macrophages, cytokines released by reactive astrocytes can shift T cells to adopt either a more beneficial or detrimental phenotype. For example, reactive astrocytes during autoimmunity release pro-inflammatory cytokines, including TNF, IFN-γ, and IL-17, which may induce T cells to adopt a more pro-inflammatory state. However, astrocytes have also been shown to release IL-10 that shifts T cells towards the anti-inflammatory spectrum [23, 24, 32, 118, 119]. Similarly, in a murine spinal cord injury model reactive astrocytes have been shown to release anti-inflammatory TGF-β [31]. Further studies examining the influences of reactive astrocytes on T cells are needed to better understand the long-term effects of astrogliosis on adaptive immune cells during CNS recovery

Reactive astrocytes can release a variety of molecular signals that contribute to the inflammatory state of the CNS after injury or disease by directly activating immune defenses with the release of cytokines, chemokines, and other growth factors (**Table 2**). Recent advancements in astrocyte transcriptome analysis have begun to reveal the context specific production of pro-inflammatory molecules by astrocytes as well as molecular triggers that induce their production. Analysis of the astrocyte transcriptome after *in vivo* exposure to lipopolysaccharide (LPS) or infection significantly promoted the production of a pro-inflammatory, neurotoxic molecular profile [26, 52]. However, the astrocyte transcriptome shifts towards an anti-inflammatory, neuroprotective profile in an *in vivo* ischemia model [52]. Future studies should utilize single-cell sequencing techniques to transcriptionally define individual astrocyte responses during health and

Despite the number of astrocyte transcriptome data available, few studies have attempted to elucidate mechanisms and signaling cascades that mediate astrocyte pro-inflammatory production. Recent studies have indicated NFκB and SOC3 as transcriptional regulators of pro-inflammatory astrocytes after a traumatic brain injury and during autoimmune inflammation [31, 32, 37]. In a model of autoimmunity, genetic deletion of astrocyte derived NFκB results in increased expression of ECM components and pro-inflammatory cytokines [129]. Astrocytes have also been shown to release CCL2 and CXCL10 to recruit perivascular leukocytes during autoimmune inflammation [124–126]. While the role of CCL2 and CXCL10 is diverse, evidence suggests that these molecules produced by astrocytes promote leukocyte migration in the CNS parenchyma [124]. In an autoimmune inflammation model, IL-17 inflammatory induction has been shown to be mediated by astrocyte Act1 signaling. Genetically deleting Act1/IL-17 signaling from astrocytes in an EAE model prevents the induction of pro-inflammatory cytokines [28]. Reactive astrocytes can also shift towards a more pro-inflammatory state by overexpressing pro-inflammatory cytokines. In spinal cord injury and autoimmune models, the overexpression of IL-6 in astrocytes leads to increased immune cell infiltration. The proinflammatory cytokine, IL-1β, produced by astrocytes, has also been shown to initiate a signaling cascade that releases vasoactive endothelial growth factor (VEGF), leading to increased BBB permeability and leukocyte leakage [127, 128]. In general, there is also evidence that astrocytes contribute to triggering inflammatory responses due to increases in neuronal activity in epilepsy, neuropathic pain, and

**7. Reactive astrocytes as a pro-inflammatory regulator**

**116**

stress [130].


*As immune-competent cells, astrocytes can detect injury signals and respond with the release of cytokine, chemokines, and growth factors as well initiating intracellular signaling pathways. Data suggests that the downstream effects of astrocyte activation is context- and time-dependent, and that both factors as well as other microenvironment stimuli can shift reactive astrocytes to either a more beneficial or detrimental phenotype.*

*Act = actin, CCL = chemokine (C-C motif), CXCL = chemokine (C-X-C motif) ligand, Gp = glycoprotein, IL = interleukin, IFN = interferon, NFκB = nuclear factor kappa B, EAE = experimental autoimmune encephalomyelitis, SHH = sonic hedgehog, Soc3 = suppressor of cytokine signaling 3, STAT3 = signaling transducer and activator of transcription 3, TGF = transforming growth factor β, TNF = tumor necrosis factor, VEGF = vascular endothelial growth factor.*

### **Table 2.**

*Pro- and anti-immune responses of astrocyte molecules.*

### **8. Reactive astrocytes as an anti-inflammatory regulator**

Despite the growing body of work that suggests pro-inflammatory roles for astrocytes, there is an equal amount of evidence suggesting these cells limit inflammation. Recent loss-of-function experiments have also revealed essential anti-inflammatory roles of astrocytes after a variety of CNS injury and disease states (**Table 2**). These studies have also revealed specific molecular mechanisms that mediate these anti-inflammatory roles. The astrocyte TGF-β response seems to selectively affect astrocyte cytokine and chemokine production after ischemia in murine models. The genetic deletion of TGF-β signaling in astrocytes leads to diffused inflammation and enhances myeloid cell activation [43, 44]. After toxoplasmic encephalitis, the genetic loss of astrocyte TGF-β signaling can lead to the increase of infiltrating T cells. Notably, in both examples, astrocyte TGF-β signaling controls infiltration immune cell number but not necessarily

the immune response profile. Astrocyte signaling involving gp130, a receptor for IL-6, or estrogen receptor 1α has also been shown to be anti-inflammatory. In autoimmune and infection models, the genetic deletion of gp130 from astrocytes results in increased inflammatory cytokine production [24, 25]. Similar outcomes, such as increased myeloid infiltration and mortality, are observed in autoimmune models when estrogen receptor 1α is conditional deleted from astrocytes [23]. During autoimmunity, mice deficient in functional IFNγ signaling in astrocytes result in exacerbated disease and mortality due to enhanced leukocyte infiltration and an upregulation of inflammatory gene expression, including CCL1, CCL5, CXC10, and TNF [119]. These mice also had a reduction in anti-inflammatory cytokines, such as IL-10 and IL-27, when compared to mice with functional IFNγ in astrocytes [119].

### **9. Reactive astrocytes as a neuroprotector of the CNS**

In addition to astrocyte regulation of the immune response, these glial cells can respond to CNS injury by altering neuronal function or survival. Neuronal insults result in the release of numerous signals, including increased glutamate production, ATP release and vascular damage. During numerous CNS disease states, including stroke, traumatic injury, epilepsy, neurodegeneration, and viral infection, injured and dying neurons release glutamate, which is harmful to neurons [131–134]. Astrocytes have been shown to take up excessive extracellular glutamate and dampen the neurotransmitter's excitotoxicity on neurons, resulting in decreased neuronal death [135]. *In vitro* studies have also shown that glutamate signaling in astrocytes decrease their production of CCL5, a T cell chemoattractant, reducing overall neuroinflammation [136].

### **10. Reactive astrocytes as a neurotoxin of the CNS**

Inflammation itself can unfortunately impair astrocyte uptake of glutamate, which leads to increased neuronal toxicity and a positive feedback of neuroinflammation [137]; for example, in an *in vitro* study TNF, released by microglia, signals to astrocyte to release glutamate, increasing excitotoxicity [138]. Neuronal injury and death also lead to the release of potassium and ATP. Both potassium and ATP can activate the inflammasome complex, which is an innate immune mechanism that when activated, resulting in the production of proinflammatory cytokines and increased inflammatory responses. The activation of the inflammasome complex, in this case, is through pannexin 1 channels, expressed by astrocytes [139, 140]. Pannexin 1 channels are opened by potassium and ATP, and once opened, activate the inflammasome complex, leading to the increased production of pro-inflammatory mediators, such as IL-1β, reactive oxygen and nitrogen species, and CCL2, a myeloid cell chemoattractant [139, 141–143]. ATP also can induce the release of glutamate from astrocytes, which can contribute to overall excitotoxicity [144]. During health, astrocytes release stored glycogen which is converted to lactate and transported to metabolically support neurons [145]. Neurons can resist excitotoxicity when astrocytes increase their glycogen uptake and lactate delivery [146]. Pro-inflammatory cytokines, including IL-1β as well as IFN-γ, TNF, and IL-6, negatively impacts this process by reducing glycogen storage and lactate transport in astrocytes that is necessary as an energy source of neurons [147, 148].

**119**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

immune pathways influence astrocyte reactivity.

this process on health and disease are unknown.

ATP adenosine triphosphate BAFF B-cell activating factor BBB blood-brain barrier

CNS central nervous system

ECM extracellular matrix EGF epidermal growth factor FGF fibroblast growth factor GFAP glial fibrillary acid protein

IFN interferon IL interleukin

CCL chemokine (C-C motif) ligand CCR chemokine (C-C motif) receptor

CSPG chondroitin sulfate proteoglycan CXCL chemokine (C-X-C motif) ligand CXCR chemokine (C-X-C motif) receptor DAMP damage-associated molecular pattern

cAMP cyclic AMP

Despite the recent advances in defining the role of astrocytes in regulating neuroinflammation, our understanding of these complex glial cells is only beginning. A few studies have demonstrated astrocyte polarization after various CNS injuries [26, 52, 95]. In this model, "A1" reactive astrocytes are pro-inflammatory, neurotoxic while "A2" reactive astrocytes are anti-inflammatory, neuroprotective. Future research, however, is needed to determine whether, like the inflammatory microglia and macrophages, reactive astrocytes shift phenotypes along a spectrum of responses. The amount of new technology available to researchers will also make it possible to further dissect the complexity of astrocytes. Single-cell transcriptional profiling techniques, specifically, can be used as a tool to identify astrocyte subtypes as well as intracellular signaling networks. This method has already been utilized to reveal distinct astrocyte types with regionally restricted distribution in the healthy mouse brain [149]. A key goal, however, for researchers in the future will be to elucidate signaling networks that are relevant to CNS injury and disease and how

While current research focuses primarily on astrocyte interactions with other CNS cell types, such as neurons, microglia, pathogens and infiltrating immune cells, future studies will need to examine how other biologic variables, including age and sex, influence astrocyte effects within the central and peripheral immune systems. Additionally, there is already some evidence that astrocyte immune regulation is influenced by the gut microbiome [150], but the implications and effects of

In summary, astrocytes exhibit diverse and sometimes conflicting roles in the setting of neuroinflammatory diseases. These multipurpose glia cells not only sense and influence damaged neurons but appear to summate multiple signals to develop specific responses that modulate neuroinflammation. It is our hope that understanding how astrocytes receive and response to information as they perform these differential roles will lead to therapies that specifically target astrocytes during CNS

**11. Conclusions**

injury and disease.

**Abbreviations**

### **11. Conclusions**

*Glia in Health and Disease*

in astrocytes [119].

overall neuroinflammation [136].

the immune response profile. Astrocyte signaling involving gp130, a receptor for IL-6, or estrogen receptor 1α has also been shown to be anti-inflammatory. In autoimmune and infection models, the genetic deletion of gp130 from astrocytes results in increased inflammatory cytokine production [24, 25]. Similar outcomes, such as increased myeloid infiltration and mortality, are observed in autoimmune models when estrogen receptor 1α is conditional deleted from astrocytes [23]. During autoimmunity, mice deficient in functional IFNγ signaling in astrocytes result in exacerbated disease and mortality due to enhanced leukocyte infiltration and an upregulation of inflammatory gene expression, including CCL1, CCL5, CXC10, and TNF [119]. These mice also had a reduction in anti-inflammatory cytokines, such as IL-10 and IL-27, when compared to mice with functional IFNγ

In addition to astrocyte regulation of the immune response, these glial cells can respond to CNS injury by altering neuronal function or survival. Neuronal insults result in the release of numerous signals, including increased glutamate production, ATP release and vascular damage. During numerous CNS disease states, including stroke, traumatic injury, epilepsy, neurodegeneration, and viral infection, injured and dying neurons release glutamate, which is harmful to neurons [131–134]. Astrocytes have been shown to take up excessive extracellular glutamate and dampen the neurotransmitter's excitotoxicity on neurons, resulting in decreased neuronal death [135]. *In vitro* studies have also shown that glutamate signaling in astrocytes decrease their production of CCL5, a T cell chemoattractant, reducing

Inflammation itself can unfortunately impair astrocyte uptake of glutamate, which leads to increased neuronal toxicity and a positive feedback of neuroinflammation [137]; for example, in an *in vitro* study TNF, released by microglia, signals to astrocyte to release glutamate, increasing excitotoxicity [138]. Neuronal injury and death also lead to the release of potassium and ATP. Both potassium and ATP can activate the inflammasome complex, which is an innate immune mechanism that when activated, resulting in the production of proinflammatory cytokines and increased inflammatory responses. The activation of the inflammasome complex, in this case, is through pannexin 1 channels, expressed by astrocytes [139, 140]. Pannexin 1 channels are opened by potassium and ATP, and once opened, activate the inflammasome complex, leading to the increased production of pro-inflammatory mediators, such as IL-1β, reactive oxygen and nitrogen species, and CCL2, a myeloid cell chemoattractant [139, 141–143]. ATP also can induce the release of glutamate from astrocytes, which can contribute to overall excitotoxicity [144]. During health, astrocytes release stored glycogen which is converted to lactate and transported to metabolically support neurons [145]. Neurons can resist excitotoxicity when astrocytes increase their glycogen uptake and lactate delivery [146]. Pro-inflammatory cytokines, including IL-1β as well as IFN-γ, TNF, and IL-6, negatively impacts this process by reducing glycogen storage and lactate transport in astrocytes that is necessary as an energy source of

**9. Reactive astrocytes as a neuroprotector of the CNS**

**10. Reactive astrocytes as a neurotoxin of the CNS**

**118**

neurons [147, 148].

Despite the recent advances in defining the role of astrocytes in regulating neuroinflammation, our understanding of these complex glial cells is only beginning. A few studies have demonstrated astrocyte polarization after various CNS injuries [26, 52, 95]. In this model, "A1" reactive astrocytes are pro-inflammatory, neurotoxic while "A2" reactive astrocytes are anti-inflammatory, neuroprotective. Future research, however, is needed to determine whether, like the inflammatory microglia and macrophages, reactive astrocytes shift phenotypes along a spectrum of responses. The amount of new technology available to researchers will also make it possible to further dissect the complexity of astrocytes. Single-cell transcriptional profiling techniques, specifically, can be used as a tool to identify astrocyte subtypes as well as intracellular signaling networks. This method has already been utilized to reveal distinct astrocyte types with regionally restricted distribution in the healthy mouse brain [149]. A key goal, however, for researchers in the future will be to elucidate signaling networks that are relevant to CNS injury and disease and how immune pathways influence astrocyte reactivity.

While current research focuses primarily on astrocyte interactions with other CNS cell types, such as neurons, microglia, pathogens and infiltrating immune cells, future studies will need to examine how other biologic variables, including age and sex, influence astrocyte effects within the central and peripheral immune systems. Additionally, there is already some evidence that astrocyte immune regulation is influenced by the gut microbiome [150], but the implications and effects of this process on health and disease are unknown.

In summary, astrocytes exhibit diverse and sometimes conflicting roles in the setting of neuroinflammatory diseases. These multipurpose glia cells not only sense and influence damaged neurons but appear to summate multiple signals to develop specific responses that modulate neuroinflammation. It is our hope that understanding how astrocytes receive and response to information as they perform these differential roles will lead to therapies that specifically target astrocytes during CNS injury and disease.

### **Abbreviations**



## **Author details**

Allison Soung1 and Robyn S. Klein1,2,3\*

1 Department of Internal Medicine, Washington University School of Medicine, United States

2 Department of Pathology and Immunology, Washington University School of Medicine, United States

3 Department of Neuroscience, Washington University School of Medicine, United States

\*Address all correspondence to: rklein@wustl.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**121**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

> [10] Sofroniew MV. Astrogliosis. Cold Spring Harbor Perspectives in Biology.

[11] Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia.

[12] Kang W, Hébert JM. Signaling pathways in reactive astrocytes, a genetic perspective. Molecular Neurobiology. 2011;**43**(3):147-154

[13] Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neuroscience Letters. 2014;**565**:23-29

[14] Pekny M et al. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. The Journal of Cell Biology.

[15] Sofroniew MV. Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. The Neuroscientist. 2014;**20**(2):160-172

[16] Pekny M et al. Astrocytes: A central element in neurological diseases. Acta Neuropathologica.

[17] Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron.

[18] Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscience. 2005;**11**(5):400-407

[19] Silver J, Miller JH. Regeneration beyond the glial scar. Nature Reviews. Neuroscience. 2004;**5**(2):146-156

[20] Silver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: Role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harbor Perspectives in Biology.

2015;**7**(2):a020420

2005;**50**(4):427-434

1999;**145**(3):503-514

2016;**131**(3):323-345

2014;**81**(2):229-248

2015;**7**(3):a020602

[1] Klein RS, Fricker LD. Heterogeneous

expression of car ypeptidase E and proenkephalin mRNAs by cultured astrocytes. Brain Research.

[2] Bindocci E, Savtchouk I, Liaudet N, Becker D, Carriero G, Volterra A. Neuroscience: Threedimensional Ca2+ imaging advances understanding of astrocyte biology. Science. 2017;**356**(6339):eaai8185

[3] Yoon H, Walters G, Paulsen AR, Scarisbrick IA. Astrocyte heterogeneity across the brain and spinal cord occurs developmentally, in adulthood and in response to demyelination. PLoS One.

[4] Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nature Neuroscience.

[5] Hurwitz AA, Berman JW,

[6] Barres BA. The mystery and magic of glia: A perspective on their roles in health and disease. Neuron.

[7] Sofroniew MV, Vinters HV.

Astrocytes: Biology and pathology. Acta Neuropathologica. 2010;**119**(1):7-35

[8] Liddelow SA, Barres BA. Reactive astrocytes: Production, function, and therapeutic potential. Immunity.

[9] Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends in Neurosciences.

2008;**60**(3):430-440

2017;**46**(6):957-967

2009;**32**(12):638-647

Rashbaum WK, Lyman WD. Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells. Brain Research. 1993;**625**(2):238-243

1992;**569**(2):300-310

2017;**12**(7):e0180697

2013;**16**(12):1773-1782

**References**

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

### **References**

*Glia in Health and Disease*

ISG interferon-stimulated gene KSPG keratan sulfate proteoglycan MMP9 matric metallopeptidase 9 NFκB nuclear factor kappa B NPC neural progenitor cell

PPR pattern recognition receptor RIG-I retinoic acid-inducible gene I

SOC3 suppressor of cytokine signaling 3

TGF-β transforming growth factor beta

VEGF vasoactive endothelial growth factor

STAT3 signal transducer and activator of transcription 3

RLRs RIG-I-like receptor SGZ subgranular zone SHH sonic hedge hog

SVZ subventricular zone

TLR toll-like receptor TNF tumor necrosis factor

PAMP pathogen-associated molecular pattern

**120**

**Author details**

Allison Soung1

United States

United States

Medicine, United States

and Robyn S. Klein1,2,3\*

\*Address all correspondence to: rklein@wustl.edu

provided the original work is properly cited.

1 Department of Internal Medicine, Washington University School of Medicine,

2 Department of Pathology and Immunology, Washington University School of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

3 Department of Neuroscience, Washington University School of Medicine,

[1] Klein RS, Fricker LD. Heterogeneous expression of car ypeptidase E and proenkephalin mRNAs by cultured astrocytes. Brain Research. 1992;**569**(2):300-310

[2] Bindocci E, Savtchouk I, Liaudet N, Becker D, Carriero G, Volterra A. Neuroscience: Threedimensional Ca2+ imaging advances understanding of astrocyte biology. Science. 2017;**356**(6339):eaai8185

[3] Yoon H, Walters G, Paulsen AR, Scarisbrick IA. Astrocyte heterogeneity across the brain and spinal cord occurs developmentally, in adulthood and in response to demyelination. PLoS One. 2017;**12**(7):e0180697

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[6] Barres BA. The mystery and magic of glia: A perspective on their roles in health and disease. Neuron. 2008;**60**(3):430-440

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[8] Liddelow SA, Barres BA. Reactive astrocytes: Production, function, and therapeutic potential. Immunity. 2017;**46**(6):957-967

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[12] Kang W, Hébert JM. Signaling pathways in reactive astrocytes, a genetic perspective. Molecular Neurobiology. 2011;**43**(3):147-154

[13] Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neuroscience Letters. 2014;**565**:23-29

[14] Pekny M et al. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. The Journal of Cell Biology. 1999;**145**(3):503-514

[15] Sofroniew MV. Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. The Neuroscientist. 2014;**20**(2):160-172

[16] Pekny M et al. Astrocytes: A central element in neurological diseases. Acta Neuropathologica. 2016;**131**(3):323-345

[17] Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;**81**(2):229-248

[18] Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscience. 2005;**11**(5):400-407

[19] Silver J, Miller JH. Regeneration beyond the glial scar. Nature Reviews. Neuroscience. 2004;**5**(2):146-156

[20] Silver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: Role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harbor Perspectives in Biology. 2015;**7**(3):a020602

[21] Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience. 2006;**7**(8):617-627

[22] Hamby ME, Sofroniew MV. Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics. 2010;**7**(4):494-506

[23] Spence RD et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**(21):8867-8872

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[25] Drögemüller K et al. Astrocyte gp130-expression is critical for the control of toxoplasma encephalitis. BMC Proceedings. 2008;**2**(Suppl 1):S10

[26] Garber C, Vasek MJ, Vollmer LL, Sun T, Jiang X, Klein RS. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1 article. Nature Immunology. 2018;**19**(2):151-161

[27] Herx LM, Yong VW. Interleukin-1β is required for the early evolution of reactive astrogliosis following CNS lesion. Journal of Neuropathology and Experimental Neurology. 2001;**60**(10):961-971

[28] Kang Z et al. Astrocyte-restricted ablation of interleukin-17-induced act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity. 2010;**32**(3):414-425

[29] Balasingam V, Tejada-Berges T, Wright E, Bouckova R, Yong V. Reactive astrogliosis in the neonatal mouse

brain and its modulation by cytokines. The Journal of Neuroscience. 1994;**14**(2):846-856

[30] Gimenez MAT, Sim JE, Russell JH. TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation. Journal of Neuroimmunology. 2004;**151**(1):116-125

[31] Brambilla R et al. Transgenic inhibition of astroglial NF-κB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. Journal of Immunology. 2009;**182**(5):2628-2640

[32] Brambilla R et al. Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. The Journal of Experimental Medicine. 2005;**202**(1):145-156

[33] Dvoriantchikova G et al. Inactivation of astroglial NF-κB promotes survival of retinal neurons following ischemic injury. The European Journal of Neuroscience. 2009;**30**(2):175-185

[34] Shimada IS, Borders A, Aronshtam A, Spees JL. Proliferating reactive astrocytes are regulated by notch-1 in the peri-infarct area after stroke. Stroke. 2011;**42**(11):3231-3237

[35] Shimada IS, LeComte MD, Granger JC, Quinlan NJ, Spees JL. Selfrenewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. The Journal of Neuroscience. 2012;**32**(23):7926-7940

[36] Alvarez JI et al. The hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science. 2011;**334**(6063):1727-1731

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*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

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Galles K, Galbreath EJ, Goldman JE, Brenner M. Fatal encephalopathy with astrocyte inclusions in GFAP transgenic

[47] Gao K et al. Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression. Glia.

Gallo V. Endothelin-1 regulates astrocyte

[49] Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH. IL-6-type cytokines enhance epidermal growth factorstimulated astrocyte proliferation. Glia.

[50] Sirko S et al. Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem

Rebec GV. Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: Interactions between neurons and astrocytes. Basal

[52] Liddelow SA et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;**541**(7638):481-487

[53] Röhl C, Lucius R, Sievers J. The effect of activated microglia on astrogliosis parameters in astrocyte cultures. Brain

2014;**94**(4):1077-1098

2013;**61**(12):2063-2077

2000;**32**(3):328-337

Cell. 2013;**12**(4):426-439

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Ganglia. 2012;**2**(2):57-66

Research. 2007;**1129**:43-52

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[39] Herrmann JE et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of Neuroscience.

[40] Anderson MA et al. Astrocyte scar formation AIDS central nervous system axon regeneration. Nature.

[41] Schachtrup C et al. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. The Journal of Neuroscience. 2010;**30**(17):5843-5854

[42] Wang Y, Moges H, Bharucha Y, Symes A. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Experimental Neurology. 2007;**203**(1):168-184

[43] Cekanaviciute E, Fathali N, Doyle KP, Williams AM,

Han J, Buckwalter MS. Astrocytic transforming growth factorbeta signaling reduces subacute

Glia. 2014;**62**(8):1227-1240

2014;**193**(1):139-149

neuroinflammation after stroke in mice.

[44] Cekanaviciute E et al. Astrocytic TGF-β signaling limits inflammation and reduces neuronal damage during central nervous system toxoplasma infection. Journal of Immunology.

2008;**28**(28):7231-7243

2016;**532**(7598):195-200

2006;**12**(7):829-834

*Astrocytes: Initiators of and Responders to Inflammation DOI: http://dx.doi.org/10.5772/intechopen.89760*

[37] Okada S et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Medicine. 2006;**12**(7):829-834

*Glia in Health and Disease*

2010;**7**(4):494-506

2011;**108**(21):8867-8872

2008;**2**(Suppl 1):S10

2018;**19**(2):151-161

2001;**60**(10):961-971

[21] Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience. 2006;**7**(8):617-627

brain and its modulation by cytokines.

Russell JH. TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation. Journal of Neuroimmunology.

[31] Brambilla R et al. Transgenic inhibition of astroglial NF-κB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system

inflammation. Journal of Immunology.

[32] Brambilla R et al. Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. The Journal of Experimental Medicine.

The Journal of Neuroscience.

[30] Gimenez MAT, Sim JE,

1994;**14**(2):846-856

2004;**151**(1):116-125

2009;**182**(5):2628-2640

2005;**202**(1):145-156

2009;**30**(2):175-185

[33] Dvoriantchikova G et al. Inactivation of astroglial NF-κB promotes survival of retinal neurons following ischemic injury. The European Journal of Neuroscience.

[34] Shimada IS, Borders A,

[35] Shimada IS, LeComte MD,

renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. The Journal of Neuroscience.

[36] Alvarez JI et al. The hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science. 2011;**334**(6063):1727-1731

2012;**32**(23):7926-7940

Aronshtam A, Spees JL. Proliferating reactive astrocytes are regulated by notch-1 in the peri-infarct area after stroke. Stroke. 2011;**42**(11):3231-3237

Granger JC, Quinlan NJ, Spees JL. Self-

[22] Hamby ME, Sofroniew MV. Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics.

[23] Spence RD et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proceedings of the National Academy of Sciences of the United States of America.

[24] Haroon F et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. Journal of Immunology. 2011;**186**(11):6521-6531

[25] Drögemüller K et al. Astrocyte gp130-expression is critical for the control of toxoplasma encephalitis. BMC Proceedings.

[26] Garber C, Vasek MJ, Vollmer LL, Sun T, Jiang X, Klein RS. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1 article. Nature Immunology.

[27] Herx LM, Yong VW. Interleukin-1β is required for the early evolution of reactive astrogliosis following CNS lesion. Journal of Neuropathology and Experimental Neurology.

[28] Kang Z et al. Astrocyte-restricted ablation of interleukin-17-induced act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity. 2010;**32**(3):414-425

[29] Balasingam V, Tejada-Berges T, Wright E, Bouckova R, Yong V. Reactive astrogliosis in the neonatal mouse

**122**

[38] Wanner IB et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. The Journal of Neuroscience. 2013;**33**(31):12870-12886

[39] Herrmann JE et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of Neuroscience. 2008;**28**(28):7231-7243

[40] Anderson MA et al. Astrocyte scar formation AIDS central nervous system axon regeneration. Nature. 2016;**532**(7598):195-200

[41] Schachtrup C et al. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. The Journal of Neuroscience. 2010;**30**(17):5843-5854

[42] Wang Y, Moges H, Bharucha Y, Symes A. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Experimental Neurology. 2007;**203**(1):168-184

[43] Cekanaviciute E, Fathali N, Doyle KP, Williams AM, Han J, Buckwalter MS. Astrocytic transforming growth factorbeta signaling reduces subacute neuroinflammation after stroke in mice. Glia. 2014;**62**(8):1227-1240

[44] Cekanaviciute E et al. Astrocytic TGF-β signaling limits inflammation and reduces neuronal damage during central nervous system toxoplasma infection. Journal of Immunology. 2014;**193**(1):139-149

[45] Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: Costs and benefits. Physiological Reviews. 2014;**94**(4):1077-1098

[46] Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M. Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. The American Journal of Pathology. 1998;**152**(2):391-398

[47] Gao K et al. Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression. Glia. 2013;**61**(12):2063-2077

[48] Gadea A, Schinelli S, Gallo V. Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. The Journal of Neuroscience. 2008;**28**(10):2394-2408

[49] Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH. IL-6-type cytokines enhance epidermal growth factorstimulated astrocyte proliferation. Glia. 2000;**32**(3):328-337

[50] Sirko S et al. Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem Cell. 2013;**12**(4):426-439

[51] Estrada-Sánchez AM, Rebec GV. Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: Interactions between neurons and astrocytes. Basal Ganglia. 2012;**2**(2):57-66

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2012;**12**(9):623-635

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2015;**10**(11):3270-3285

2008;**226**:41-56

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regulated by interferon-γ. Acta

168-175

monocyte chemoattractant

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2003;**22**(3):319-330

545-558

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2006;**2**(12):679-689

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Inflammatory CNS reactions in response to neuronal activity. Nature Reviews Neuroscience. 2014;**15**(1):43-53

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**128**

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[136] Besong G et al. Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures. The Journal of Neuroscience. 2002;**22**(13):5403-5411

[137] Prow NA, Irani DN. The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis. Journal of Neurochemistry. 2008;**105**(4):1276-1286

[138] Bezzi P et al. CXCR4-activated astrocyte glutamate release via TNFa: Amplification by microglia triggers neurotoxicity. Nature Neuroscience. 2001;**4**(7):702-710

[139] Minkiewicz J, de Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013;**61**(7):1113-1121

[140] Kido Y et al. Regulation of activity of P2X7 receptor by its splice variants in cultured mouse astrocytes. Glia. 2014;**62**(3):440-451

[141] Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. The EMBO Journal. 2006;**25**(21):5071-5082

[142] Silverman WR et al. The pannexin 1 channel activates the inflammasome in neurons and astrocytes. The Journal of Biological Chemistry. 2009;**284**(27):18143-18151

[143] Xia M, Zhu Y. FOXO3a involvement in the release of TNF-α stimulated by ATP in spinal cord astrocytes. Journal of Molecular Neuroscience. 2013;**51**(3):792-804

[144] Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocytemediated modulation of excitatory neurotransmission. Proceedings of the National Academy of Sciences. 2012;**109**(4):E197-E205

[145] Pellerin L et al. Evidence supporting the existence of an activitydependent astrocyte-neuron lactate shuttle. Developmental Neuroscience. 1998;**20**(4-5):291-299

[146] Bliss TM et al. Dual-gene, dualcell type therapy against an excitotoxic insult by bolstering neuroenergetics. The Journal of Neuroscience. 2004;**24**(27):6202-6208

[147] Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metabolism. 2011;**14**(6):724-738

[148] Gavillet M, Allaman I, Magistretti PJ. Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia. 2008;**56**(9):975-989

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**131**

**Chapter 7**

**Abstract**

using cell-based therapies.

**1. Multiple sclerosis**

Astrocytes in Pathogenesis of

*Izrael Michal, Slutsky Shalom Guy and Revel Michel*

Translation into Clinic

Multiple Sclerosis and Potential

Astrocytes are the most abundant glial cells in the central nervous system (CNS) and play a pivotal role in CNS homeostasis and functionality. Malfunction of astrocytes was implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). The involvement of astrocytes in the pathology of neurodegenerative disorders supports the rationale of transplantation of healthy human astrocytes that can potentially compensate for diseased endogenous astrocytes. In this review, we will focus on the roles of astrocytes in the healthy CNS and under MS conditions. We will describe the cell sources and current cell-based therapies for MS with a focus on the potential of astrocyte transplantation. In addition, we will cover immerging early-stage clinical trials in MS that are currently being conducted

**Keywords:** astrocytes, multiple sclerosis, neurodegenerative diseases, autologous

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating, and degenerative disease of the CNS. The disease leads to permanent neurological disability, including limb weakness, sensory loss, vision disturbances, pain, and muscle spasms [1]. MS is affecting more than 2 million people worldwide, most of them are females between the age of 20 and 40 years. The most prevalent clinical course of the disease (approximately 80% of the cases) is relapsing-remitting MS (RRMS), characterized by a period of functional disability (relapses) and followed by spontaneous improvements (remissions) [1]. With the progression of the disease, most of the patients will develop a course of secondary progressive MS (SPMS), characterized by a steady decline in neurological function, with no phases of remissions [2]. A less common form of MS is primary progressive MS (PPMS), representing approximately 10% of MS cases. PPMS is characterized by a development of gradual progressive disease with no remission phases [2, 3]. Currently, 15 disease-modifying treatments (DMTs) are approved by the FDA for the treatment of MS [4]. The mechanisms of action of these DMTs are diverse; however, they all aim to modulate or suppress the immune system. The current DMTs have benefit in reducing frequency and severeness of relapses and buildup of disability in RRMS; nevertheless, they have only limited impact on the progressive forms of MS [2, 5, 6].

hematopoietic stem cells (AHSC), mesenchymal stem cells (MSC)

### **Chapter 7**

*Glia in Health and Disease*

2018;**174**:999-1014

2016;**22**(6):586-597

of the mouse nervous system. Cell.

[150] Rothhammer V et al. Type i interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nature Medicine.

[151] Engelhardt B, Coisne C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids and

Barriers of the CNS. 2011;**8**(1):4

**130**
