**1. Introduction**

The aging of the world population has been demonstrated systematically by several demographic studies. Regrettably, increased life expectancy has led to an increased prevalence of age-related disorders including neurodegenerative diseases. In this regard, Alzheimer's and Parkinson's diseases constitute the most relevant issues for the public health system of different countries. Accordingly, during the last decades, significant efforts have been committed to improve our understanding of the molecular cascades responsible for an altered aging process as well as for the

establishment and progression of neurodegenerative disorders, mainly Alzheimer's disease (AD) and Parkinson's disease (PD) [1].

Relevantly, though AD and PD possess their very own pathological characteristics, the neuroinflammatory milieu has emerged as a central event of the chronic degenerative process. From the prodromal stage of these disorders up to the more advanced ones, inflammation seems to accompany or, in some cases, to drive the progression of AD and PD. Importantly, inflammation, as part of the nonspecific immune response, plays a critical role in maintenance of system homeostasis, allowing to prevent or to control the detrimental effects induced by a wide variety of xenobiotics to the cellular components of the biological systems. Remarkably, from an unspecific harmful stimulus, a whole range of responses are triggered including complement cascade activation and cytokines release as well as activation of the immune cells located at the site of the insult. To properly eliminate the initial cause of distress and to repair the damaged tissue, the inflammatory response must be delicately balanced considering not only pro-inflammatory but anti-inflammatory mediators as well. Tumor necrosis factor 1 (TNF-1α), interleukins (IL-1, IL-8, IL-10), interferon (INF-γ), transforming growth factor 1 (TGF-1), complement proteins, act together to develop a coordinated response against primary, unspecific stimuli [2, 3]. In this regard, the compromise of this essential system relates with severe, and often lethal, conditions including immunodeficiency syndromes as well as autoimmune diseases. Relevantly, during the last decades, a lot of attention has been also given to the effects of chronic inflammatory condition as the starting point of different degenerative conditions. Among these, neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, have found in the inflammatory response a critical milieu of events able to determinate the main molecular and cellular events verified during each of these diseases [4].

### **2. Central nervous system (CNS) immunocompetence**

CNS is a highly specialized structure whose functions require specific microenvironmental conditions. Moreover, neuronal activity and, thus, the health of the neuronal network depend on the maintenance of ion gradients whose concentration differs significantly from the rest of the body compartments [5]. To ensure these conditions, the CNS remains partially isolated by the existence of the blood-brain barrier (BBB), a highly complex semipermeable cellular barrier whose main function is to prevent both exogenous and endogenous elements to alter the brain homeostasis [5–7]. Regarding the immune response, microglial population constitutes the only immune system cellular representative within the brain with the astrocytes acting as a companion to exert immune surveillance and to act as the first line of response against harmful events within the brain. Although some additional peripheral immune cells including cluster of differentiation 11b and c (CD11b, CD11c)-positive cells localize to the CNS during some inflammatory conditions, it is believed that this situation is caused because of an altered permeability of the BBB as a consequence of the primary insult [8]. In this sense, the brain parenchyma has been defined as an anti-inflammatory environment due the increased levels of relevant anti-inflammatory mediators including the transforming growth factor β (TGFβ) and interleukin (IL)-10, preventing both the immune cell spreading across the CNS and an excessively strong immune response [8–10]. However, this latter condition does not imply that the CNS cannot answer to immune challenges; on the contrary, the CNS is a fully immunocompetent system, but with this mechanism being tightly controlled in order to avoid secondary damage caused by extensive inflammation and detrimental cell damage end products, such as reactive oxygen

**85**

*Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades…*

species (ROS). In this context, during the last years, it has been evidenced that sustained inflammatory challenge, whether systemic or local to the CNS, will alter significantly the neuronal environment affecting severely the neuronal function and the health of the neuronal network. Regrettably, it has been suggested that prior to AD and PD establishment as well as during their progression, a chronic inflammatory condition has developed, contributing to the molecular alterations

A significant characteristic of AD and PD is that these pathologies exhibit a strong inflammatory component even when both are sterile conditions. In this sense, the innate immune system works through the pattern recognition receptors (PRRs) which recognize molecular patterns related to pathogens (pathogen-associated molecular patterns, PAMPs) and to endogenous molecules indicative of cell damage (damageassociated molecular patterns, DAMPs), such as high-mobility group protein B1 (HMGB1), S100 proteins, heat shock proteins (HSPs), DNA, mitochondrial DNA (mt-DNA), and ATP [11–15]. The toll-like receptors (TLRs) family constitutes a highly relevant type of PRR necessary not only to unleash the initial immune response but also to connect the first unspecific defense with the secondary adaptive immunity [12]. Depending on the species, 11–13 TLR subtypes can be found. Relevantly, the localization of these receptors within the cells differs between the different TLRs. In this regard, while TLRs 1, 2, 4, 5, and 6 are expressed at the cell membrane, its main objective being to sense the extracellular compartment, the TLRs 3, 7, 8, and 9 are located inside the cells, mainly associated with endosomes and sensing the internal microenvironment for viral components, such as RNA and DNA [12, 16]. The presence of TLRs has been determined not only in several cell components of the peripheral immune system but also in the different cell types found in the brain including astrocytes, microglia, neurons, and oligodendrocytes, suggesting that each of these cell types can sense and trigger an immune response in the presence of different harmful molecular patterns. Interestingly, it has been demonstrated that not all the cells within the brain express the same pattern of TLRs. For example, microglia and neurons express all TLR subtypes, while astrocytes express a more limited repertoire, including TLR2, TLR3, TLR4, TLR9, and TLR11 [16, 17].

The signaling cascade triggered after TLRs' activation involves the cross talk with several additional pathways able to critically modify cell physiology. In this sense, canonical TLR-mediated signaling involves the myeloid differentiation factor 88 (MyD88) cascade. In this pathway, TLR activation couples with MyD88 inducing the activation of interleukin-1 receptor-associated kinase (IRAK) and, subsequently, the activation of the tumor necrosis factor receptor-associated factor 6. This event allows the recruitment of the transforming growth factor-β-activated kinase-1 (TAK1) which, together with the TAK1-binding proteins, leads to the phosphorylation of IκB causing the activation of the IKK complex and the release of the nuclear factor-κB (NF-κB), triggering the NF-κB-dependent inflammatory response [11, 18, 19]. Importantly, TLR 3 and TLR 4 can also signal via the TIR-containing adaptor inducing interferon-β (IFN-β) (TRIF). In this additional pathway, additional to the release of NF-κB, it also causes an increased expression of IFN-β by means of the IKKε/TANK-binding kinase-1 (TBK1)-dependent phosphorylation of the interferon regulatory factor 3 and 7 (IRF3 and IRF7) [7, 19, 20].

*DOI: http://dx.doi.org/10.5772/intechopen.86167*

observed during these pathologies.

**3.1 TLR inflammatory cascade**

**3. Toll-like receptors**

*Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades… DOI: http://dx.doi.org/10.5772/intechopen.86167*

species (ROS). In this context, during the last years, it has been evidenced that sustained inflammatory challenge, whether systemic or local to the CNS, will alter significantly the neuronal environment affecting severely the neuronal function and the health of the neuronal network. Regrettably, it has been suggested that prior to AD and PD establishment as well as during their progression, a chronic inflammatory condition has developed, contributing to the molecular alterations observed during these pathologies.

## **3. Toll-like receptors**

*Toll-like Receptors*

disease (AD) and Parkinson's disease (PD) [1].

and cellular events verified during each of these diseases [4].

**2. Central nervous system (CNS) immunocompetence**

CNS is a highly specialized structure whose functions require specific microenvironmental conditions. Moreover, neuronal activity and, thus, the health of the neuronal network depend on the maintenance of ion gradients whose concentration differs significantly from the rest of the body compartments [5]. To ensure these conditions, the CNS remains partially isolated by the existence of the blood-brain barrier (BBB), a highly complex semipermeable cellular barrier whose main function is to prevent both exogenous and endogenous elements to alter the brain homeostasis [5–7]. Regarding the immune response, microglial population constitutes the only immune system cellular representative within the brain with the astrocytes acting as a companion to exert immune surveillance and to act as the first line of response against harmful events within the brain. Although some additional peripheral immune cells including cluster of differentiation 11b and c (CD11b, CD11c)-positive cells localize to the CNS during some inflammatory conditions, it is believed that this situation is caused because of an altered permeability of the BBB as a consequence of the primary insult [8]. In this sense, the brain parenchyma has been defined as an anti-inflammatory environment due the increased levels of relevant anti-inflammatory mediators including the transforming growth factor β (TGFβ) and interleukin (IL)-10, preventing both the immune cell spreading across the CNS and an excessively strong immune response [8–10]. However, this latter condition does not imply that the CNS cannot answer to immune challenges; on the contrary, the CNS is a fully immunocompetent system, but with this mechanism being tightly controlled in order to avoid secondary damage caused by extensive inflammation and detrimental cell damage end products, such as reactive oxygen

establishment and progression of neurodegenerative disorders, mainly Alzheimer's

Relevantly, though AD and PD possess their very own pathological characteristics, the neuroinflammatory milieu has emerged as a central event of the chronic degenerative process. From the prodromal stage of these disorders up to the more advanced ones, inflammation seems to accompany or, in some cases, to drive the progression of AD and PD. Importantly, inflammation, as part of the nonspecific immune response, plays a critical role in maintenance of system homeostasis, allowing to prevent or to control the detrimental effects induced by a wide variety of xenobiotics to the cellular components of the biological systems. Remarkably, from an unspecific harmful stimulus, a whole range of responses are triggered including complement cascade activation and cytokines release as well as activation of the immune cells located at the site of the insult. To properly eliminate the initial cause of distress and to repair the damaged tissue, the inflammatory response must be delicately balanced considering not only pro-inflammatory but anti-inflammatory mediators as well. Tumor necrosis factor 1 (TNF-1α), interleukins (IL-1, IL-8, IL-10), interferon (INF-γ), transforming growth factor 1 (TGF-1), complement proteins, act together to develop a coordinated response against primary, unspecific stimuli [2, 3]. In this regard, the compromise of this essential system relates with severe, and often lethal, conditions including immunodeficiency syndromes as well as autoimmune diseases. Relevantly, during the last decades, a lot of attention has been also given to the effects of chronic inflammatory condition as the starting point of different degenerative conditions. Among these, neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, have found in the inflammatory response a critical milieu of events able to determinate the main molecular

**84**

A significant characteristic of AD and PD is that these pathologies exhibit a strong inflammatory component even when both are sterile conditions. In this sense, the innate immune system works through the pattern recognition receptors (PRRs) which recognize molecular patterns related to pathogens (pathogen-associated molecular patterns, PAMPs) and to endogenous molecules indicative of cell damage (damageassociated molecular patterns, DAMPs), such as high-mobility group protein B1 (HMGB1), S100 proteins, heat shock proteins (HSPs), DNA, mitochondrial DNA (mt-DNA), and ATP [11–15]. The toll-like receptors (TLRs) family constitutes a highly relevant type of PRR necessary not only to unleash the initial immune response but also to connect the first unspecific defense with the secondary adaptive immunity [12].

Depending on the species, 11–13 TLR subtypes can be found. Relevantly, the localization of these receptors within the cells differs between the different TLRs. In this regard, while TLRs 1, 2, 4, 5, and 6 are expressed at the cell membrane, its main objective being to sense the extracellular compartment, the TLRs 3, 7, 8, and 9 are located inside the cells, mainly associated with endosomes and sensing the internal microenvironment for viral components, such as RNA and DNA [12, 16]. The presence of TLRs has been determined not only in several cell components of the peripheral immune system but also in the different cell types found in the brain including astrocytes, microglia, neurons, and oligodendrocytes, suggesting that each of these cell types can sense and trigger an immune response in the presence of different harmful molecular patterns. Interestingly, it has been demonstrated that not all the cells within the brain express the same pattern of TLRs. For example, microglia and neurons express all TLR subtypes, while astrocytes express a more limited repertoire, including TLR2, TLR3, TLR4, TLR9, and TLR11 [16, 17].

#### **3.1 TLR inflammatory cascade**

The signaling cascade triggered after TLRs' activation involves the cross talk with several additional pathways able to critically modify cell physiology. In this sense, canonical TLR-mediated signaling involves the myeloid differentiation factor 88 (MyD88) cascade. In this pathway, TLR activation couples with MyD88 inducing the activation of interleukin-1 receptor-associated kinase (IRAK) and, subsequently, the activation of the tumor necrosis factor receptor-associated factor 6. This event allows the recruitment of the transforming growth factor-β-activated kinase-1 (TAK1) which, together with the TAK1-binding proteins, leads to the phosphorylation of IκB causing the activation of the IKK complex and the release of the nuclear factor-κB (NF-κB), triggering the NF-κB-dependent inflammatory response [11, 18, 19]. Importantly, TLR 3 and TLR 4 can also signal via the TIR-containing adaptor inducing interferon-β (IFN-β) (TRIF). In this additional pathway, additional to the release of NF-κB, it also causes an increased expression of IFN-β by means of the IKKε/TANK-binding kinase-1 (TBK1)-dependent phosphorylation of the interferon regulatory factor 3 and 7 (IRF3 and IRF7) [7, 19, 20].

The main objective of these TLR-mediated processes is to regulate the expression of several pro-inflammatory and anti-inflammatory mediators including IL-1, IL-6, IL-10, IL-11, IL-12, tumor necrosis factor (TNF), TGF, IFN, CCL2, CCL5, CXCL8, and CXCL10, among others [4, 11, 18, 19].

Additionally, TLR activation can also signal through complementary molecular pathways. Indeed, TAK1 activation also induces nemo-like kinase (NLK) and the c-Jun N-terminal kinases (JNK) pathway [18–21]. Similarly, MyD88 can signal through the phosphatidylinositide-3 kinase (PI3K)/Akt pathway, modulating the activity of the glycogen synthase kinase 3 β (GSK3β) [22, 23]. On the other hand, it has been demonstrated that TLR2 and TLR4 can activate the PI3K/Akt pathway through the Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho family of GTPases [23]. Complimentarily, the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (JAK/STAT) pathway is known to respond to a variety of PAMPs/DAMPs and cytokines, including different interleukins and INF-β. Relevantly, different studies have demonstrated that several members of the TLR family can phosphorylate different STAT members, suggesting a direct modulation of the JAK/STAT pathway [24, 25]. As is possible to observe, the molecular cascades that could be triggered secondarily to TLR activation are related with critical cellular processes including cell cycle modulation, apoptosis, and cytoskeleton remodeling, among others. This situation depicts the complexity of the immune response and the relevance of its modulation in the context of different pathologies including neurodegenerative ones, such as AD and PD.
