**2.17 Peroxisome proliferator-activated γ receptor**

Peroxisome proliferator-activated γ receptor (PPARγ) regulates the transcription of several genes involved in inflammation, immune response, insulin sensitivity, and lipid metabolism. The pathways governed by PPARγ overlap the biological pathways implicated in AD pathogenesis according to various pieces of evidence. Besides, PPARγ regulates the expression of seven AD-associated genes, including ApoE, ABCA1, and ABCG1. Increasing ApoE lipid levels facilitate soluble Aβ degradation. Studies using AD animal models have suggested that PPARγ exerts direct and indirect effects on APP protein metabolism [51]. Peroxisome proliferatoractivated γ receptor is up-regulated in AD due to existing neuroinflammation and PPARγ agonists can be used in AD and shows anti-inflammatory effects, as well as improve learning and memory. Thus, PPARγ might be a significant new therapeutic target in AD treatment [52]. In addition, emerging evidence suggests that PPARγ effectively regulates microglia activation under physiological and pathological conditions, facilitating Aβ microglial phagocytosis [53]. In addition, PPARγ polymorphisms have been studied in AD; however, the results are controversial and inconclusive [54].

#### **2.18 NOD-like receptor pyrin domain-containing-3**

The NOD-like receptor pyrin domain-containing-3 (NLRP3) is the best known member of the NLR family. Importantly, APP can activate the NLRP3 inflammasome and increase NLRP3, caspase1, and IL1-β genes expression [55]. In microglia, NLRP3 activation is essential for interleukin-1β (IL1-β) maturation and subsequent inflammatory events. Besides, NLRP3 is possibly involved in AD

**115**

*Alzheimer's Disease Neuroprotection: Associated Receptors*

pathogenesis through oxidative stress [56]. One study showed that NLRP3 knockout mice were largely protected from spatial memory loss and other AD-associated sequelae, showing reduced caspase-1 and IL1-β activation, as well as increased Aβ clearance. Microglial activation by Aβ can initiate innate immune responses in CNS via NLRP3, even before the Aβ deposition. These results show an important role of the NLRP3 axis in the AD pathogenesis and suggest that NLRP3 inflammasome inhibition might be a new therapeutic intervention for the disease [57]. Non-steroidal anti-inflammatory drugs can inhibit NLRP3 inflammasome via reversible blockade of volume-regulated anionic channels in the plasma membrane, inhibiting cognitive impairment in AD mice models [58]. The loss of NLRP3 inflammasome function also reduced tau hyperphosphorylation and aggregation (involved in AD pathogenesis) by regulating tau kinases and phosphatases. Tau, in turn, activated the NLRP3 inflammasome. The intracerebral injection containing Aβ induced tau pathology in an NLRP3-dependent manner. Therefore, these data suggest an important role of NLRP3, microglia, and inflammasome activation in AD tauopathies [59]. Finally, virgin coconut oil improved hippocampal health, memory, and learning in AD mice models by inhibiting NLRP3 and reducing

Nuclear receptors family and G-protein-coupled receptors are probably the receptors families most involved with AD (**Table 1**). Additionally, the cerebral cortex is the main area where most of the receptors involved in AD express themselves. The cerebral cortex's physical area, its complexity, and its involvement with several relevant functions in AD probably justify this fact. Despite the small size of the hippocampus, this region is significantly affected in AD. While the cerebral cortex is mainly involved in decision making, subjective thinking, consequences of action assessment, perception, and attention, the hippocampus is mainly related to memory. As a key component of cortico-hippocampal networks, the perirenal cortex plays an important role in memory processes, especially familiarity-based recognition memory. Therefore, disrupted functional connectivity of this cortical region as a result of early neurodegeneration may contribute to altered brain rhythms and cognitive failures observed in the early clinical phase

Although few receptors involved with AD are expressed in the hypothalamus and amygdala (when compared to the expression in the cortex, hippocampus, pons, medulla, and basal ganglia), it is known that AD is closely associated with changes in mood and motivation. However, these associations depend on the AD stage. Most of the receptors involved with AD are expressed in more than one nervous system area, showing the involvement of several brain regions in AD. Additionally, microglia is one of the main cell types in which AD-associated receptors express themselves, highlighting the relevance of microglia in AD, especially in the removal of toxic peptides. Additionally, AD-associated receptors are involved with several metabolic pathways, which may be directly or indirectly related to the disease. The APP elimination or the blockage of pathways related to the APP synthesis is the main function performed by the receptors involved with AD (**Table 1**, **Figure 1**). Besides, many receptors are directly involved with cognitive, memory, and/or learning functions and many receptors are associated with more than one AD-related function (**Table 1**, **Figure 1**). Finally, AD-associated receptors are also related to nervous system plasticity, including neuronal and microglial survival, nervous system development (positive plasticity), and neuronal death (negative plasticity).

*DOI: http://dx.doi.org/10.5772/intechopen.91918*

oxidative stress [55].

of AD patients [11].

**3. Conclusion**

*Alzheimer's Disease Neuroprotection: Associated Receptors DOI: http://dx.doi.org/10.5772/intechopen.91918*

pathogenesis through oxidative stress [56]. One study showed that NLRP3 knockout mice were largely protected from spatial memory loss and other AD-associated sequelae, showing reduced caspase-1 and IL1-β activation, as well as increased Aβ clearance. Microglial activation by Aβ can initiate innate immune responses in CNS via NLRP3, even before the Aβ deposition. These results show an important role of the NLRP3 axis in the AD pathogenesis and suggest that NLRP3 inflammasome inhibition might be a new therapeutic intervention for the disease [57]. Non-steroidal anti-inflammatory drugs can inhibit NLRP3 inflammasome via reversible blockade of volume-regulated anionic channels in the plasma membrane, inhibiting cognitive impairment in AD mice models [58]. The loss of NLRP3 inflammasome function also reduced tau hyperphosphorylation and aggregation (involved in AD pathogenesis) by regulating tau kinases and phosphatases. Tau, in turn, activated the NLRP3 inflammasome. The intracerebral injection containing Aβ induced tau pathology in an NLRP3-dependent manner. Therefore, these data suggest an important role of NLRP3, microglia, and inflammasome activation in AD tauopathies [59]. Finally, virgin coconut oil improved hippocampal health, memory, and learning in AD mice models by inhibiting NLRP3 and reducing oxidative stress [55].

## **3. Conclusion**

*Neuroprotection - New Approaches and Prospects*

involved in the serotonergic system.

**2.16 Cannabinoid receptors**

the brain, all compromised in AD. Besides, 5HTR6 agonists have also been shown to have pro-cognitive effects. Partial or inverse agonists may produce promising cognitive effects [44, 45]. Moreover, 5HTR6 gene variants can be a genetic risk factor for late-onset AD and 5HTR6 polymorphisms are possibly involved with AD susceptibility, such as the C267T polymorphism [44]. However, there are relatively few genetic studies investigating the association between AD and gene variants

Evidence regarding the involvement of the endocannabinoid system (ECS) in the AD pathogenesis raised questions about the development of new therapeutic approaches for AD based on endocannabinoid regulation. The endocannabinoid system is composed of receptors, endogenous ligands, and enzymes, which are involved in AD pathogenesis [46]. Endocannabinoid system-directed drugs can exert beneficial effects on mood, as well as modulate neuroinflammation, synaptic plasticity, neurotoxicity, apoptosis, cell proliferation, cell differentiation, and oxidative stress [47, 48]. Moreover, cannabis tetrahydrocannabinol (THC) induces neurogenesis, removes Aβ peptides, and decreases neurofibrillary tangles. The hippocampus and microglia, key actors in dementia pathophysiology, express 1 and 2 cannabinoid receptors, respectively [49]. Type 2 cannabinoid receptor (CNR2) is overexpressed in activated microglia in different areas of the nervous system. Activated CNR2 has the potential to disrupt the AD process and treat the symptoms, reducing neurodegeneration, neuroinflammation, and improving spatial memory [50]. The role of the type 1 cannabinoid receptor (CNR1) is unclear.

However, CNR1 can up-regulate anti-apoptotic proteins in rats [49].

Peroxisome proliferator-activated γ receptor (PPARγ) regulates the transcription of several genes involved in inflammation, immune response, insulin sensitivity, and lipid metabolism. The pathways governed by PPARγ overlap the biological pathways implicated in AD pathogenesis according to various pieces of evidence. Besides, PPARγ regulates the expression of seven AD-associated genes, including ApoE, ABCA1, and ABCG1. Increasing ApoE lipid levels facilitate soluble Aβ degradation. Studies using AD animal models have suggested that PPARγ exerts direct and indirect effects on APP protein metabolism [51]. Peroxisome proliferatoractivated γ receptor is up-regulated in AD due to existing neuroinflammation and PPARγ agonists can be used in AD and shows anti-inflammatory effects, as well as improve learning and memory. Thus, PPARγ might be a significant new therapeutic target in AD treatment [52]. In addition, emerging evidence suggests that PPARγ effectively regulates microglia activation under physiological and pathological conditions, facilitating Aβ microglial phagocytosis [53]. In addition, PPARγ polymorphisms have been studied in AD; however, the results are controversial and

The NOD-like receptor pyrin domain-containing-3 (NLRP3) is the best known member of the NLR family. Importantly, APP can activate the NLRP3 inflammasome and increase NLRP3, caspase1, and IL1-β genes expression [55]. In microglia, NLRP3 activation is essential for interleukin-1β (IL1-β) maturation and subsequent inflammatory events. Besides, NLRP3 is possibly involved in AD

**2.17 Peroxisome proliferator-activated γ receptor**

**2.18 NOD-like receptor pyrin domain-containing-3**

**114**

inconclusive [54].

Nuclear receptors family and G-protein-coupled receptors are probably the receptors families most involved with AD (**Table 1**). Additionally, the cerebral cortex is the main area where most of the receptors involved in AD express themselves. The cerebral cortex's physical area, its complexity, and its involvement with several relevant functions in AD probably justify this fact. Despite the small size of the hippocampus, this region is significantly affected in AD. While the cerebral cortex is mainly involved in decision making, subjective thinking, consequences of action assessment, perception, and attention, the hippocampus is mainly related to memory. As a key component of cortico-hippocampal networks, the perirenal cortex plays an important role in memory processes, especially familiarity-based recognition memory. Therefore, disrupted functional connectivity of this cortical region as a result of early neurodegeneration may contribute to altered brain rhythms and cognitive failures observed in the early clinical phase of AD patients [11].

Although few receptors involved with AD are expressed in the hypothalamus and amygdala (when compared to the expression in the cortex, hippocampus, pons, medulla, and basal ganglia), it is known that AD is closely associated with changes in mood and motivation. However, these associations depend on the AD stage. Most of the receptors involved with AD are expressed in more than one nervous system area, showing the involvement of several brain regions in AD. Additionally, microglia is one of the main cell types in which AD-associated receptors express themselves, highlighting the relevance of microglia in AD, especially in the removal of toxic peptides. Additionally, AD-associated receptors are involved with several metabolic pathways, which may be directly or indirectly related to the disease. The APP elimination or the blockage of pathways related to the APP synthesis is the main function performed by the receptors involved with AD (**Table 1**, **Figure 1**). Besides, many receptors are directly involved with cognitive, memory, and/or learning functions and many receptors are associated with more than one AD-related function (**Table 1**, **Figure 1**). Finally, AD-associated receptors are also related to nervous system plasticity, including neuronal and microglial survival, nervous system development (positive plasticity), and neuronal death (negative plasticity).


**117**

*Alzheimer's Disease Neuroprotection: Associated Receptors*

**area in human CNS**

**Main roles in AD**

Spinal cord Promotes neurogenesis, inhibits neuronal

Cerebellum Participates in the generation and activity of APP protein in the brain [36, 37].

decreasing brain damage [38, 39].

Midbrain Participates in microglial survival, inflammatory

Basal ganglia Controls the pyramidal neurons migration during

and others [40–43].

Cerebral cortex Disrupt the AD process, reduce symptoms,

Amygdala Participates in pathways involved with lipid

pathogenesis [51–53].

Pons and medulla The NLRP3 activation leads to IL-1β and IL-18

[56–59].

repair [64].

Cerebral cortex Inhibits enzymes involved in AD, such as

apoptosis, and plays a role in protecting nerves and

response, phagocytosis, dendritic cell maturation

corticogenesis, activates TOR signaling, and regulates the GABAergic, glutamatergic, and cholinergic activity. Involved in cognition, anxiety,

neurodegeneration, neuroinflammation, and

metabolism and immune response implicated in AD etiology. PPARγ acts as a transcriptional regulator of several genes involved in AD

production that play a role in the inflammatory response and oxidative stress in AD pathogenesis.

acetylcholinesterase, 5-lipoxygenase, and monoamine oxidase. Protects neurons against oxidative stress, contributing to neuronal tissues

Role in hippocampal neurons degeneration. APP is able to increase intracellular calcium by opening calcium-permeable cationic channels in

hippocampal neurons [65].

memory, mood, among others [44, 45].

improve spatial memory [47–50].

This suggests that these receptors participate in several long-term changes in the

Cerebral cortex and hippocampus

Finally, most of the receptors involved in AD (67%) are associated with beneficial effects on the disease. These receptors include nuclear receptors, such as VDR, membrane receptors, such as TLR5, and cytoplasmic receptors, such as GABAR. Most of the AD-associated receptors are found in the membrane of nerve cells (61%). Among the neuroprotective receptors, we can highlight the vitamin D receptor, responsible for vitamin D actions. Vitamin D is increasingly recognized as a substance involved in neuronal survival, taking part in psychiatric and

nervous system (long-term plasticity) [60].

*DOI: http://dx.doi.org/10.5772/intechopen.91918*

Glucocorticoid receptor

Glucocorticoid receptor

G-protein-coupled receptor

G-protein-coupled receptor

Triggered receptor expressed on myeloid cells 2 (TREM-2) Immunoglobulins superfamily

5-hydroxytryptamine 6 receptor (5 HTR6) G-protein-coupled receptor

Cannabinoid receptor

G-protein-coupled receptor

Peroxisome proliferatoractivated γ receptor (PPARγ) Nuclear receptor family

NOD-like receptor pyrin domain-containing-3

NOD-like receptor family

Calcium sensing receptor

G-protein-coupled receptor

*Alzheimer's disease associated receptors.*

Sigma-1 receptor (σ1R) Chaperone protein

(GCRs)

family

family

family

(CNR)

family

(NLRP3)

(CaSR)

family

**Table 1.**

40 (GPR40)

**Receptor/family Main expression** 

*Neuroprotection - New Approaches and Prospects*

Acetylcholine receptors

Estrogen receptors (ER) Nuclear receptor family

Ryanodine receptor 3 (RyR3)

Gamma-Aminobutyric Acid receptor (GABAR) Ionotropic receptor

Vitamina D receptor (VDR) Nuclear receptor family

Retinoid X receptor (RXR) Nuclear receptor family

N-methyl-D-aspartate receptors (NMDAR) Ionotropic receptor

Liver X receptor β (LXR) Nuclear receptor family

Low-density lipoprotein receptor (LDLR) Lipoprotein receptor family

Oxidized low-density lipoprotein receptor 1

Lipoprotein receptor family

Toll-like receptor 4 (TLR4) Toll-like receptor family

Toll-like receptor 5 (TLR5) Toll-like receptor family

C-C chemokine receptor type 2 (CCR2)

Chemokine receptor family

Chemokine receptor CX3C 1

Chemokine receptor family

(CX3CR1)

(OLR1)

Receptor for advanced glycation end products

(RAGE) Immunoglobulins superfamily

Nicotinic Receptors

Calcium channels

(AChR)

**Receptor/family Main expression** 

**area in human CNS**

Cerebral cortex and cerebellum

Basal ganglia and hippocampus

Cerebral cortex and hippocampus

Cerebral cortex and hypothalamus

Midbrain, pons, and medulla

**Main roles in AD**

Basal ganglia Plays negative effects related to synaptic

decline [7–9].

toxicity [10–12].

Cerebral cortex Regulates learning, memory, cognitive function,

Cerebellum Contributes to neuronal death and inflammation

Interacts with APP protein and exert positive effects on memory and attention [1, 2].

Increases neural plasticity and neurogenesis, affecting cognitive functions and the brain regenerative potential. May play beneficial effects in reducing the brain inflammatory process [4–6].

transmission and synaptic plasticity. Associated with memory loss and age-related cognition

controls the glutamate release, and reduces APP

and is involved with the APP transport, oxidative stress, and cerebral blood flow [14, 15].

Interacts with SMAD3, regulating APP transcription through TGFβ signaling. Suppress

elimination, decreasing APP-induced deficits

inflammation in CNS. May play roles in neurogenesis, APP processing, and microglial

phagocytosis modulation [24–26].

Pons and medulla Mediates the increase in ApoE expression induced by APP protein [27].

Midbrain Mediates the uptake and internalization of low-

be involved in AD [27].

Hippocampus Induces CREB signaling, which regulates

Thalamus Binds to APP oligomers and fibrils, forming

Pons and medulla Promotes monocyte recruitment to APP

APP proteins [34].

functions [34].

[28, 32, 33].

Participates in CNS development and is involved in synaptic plasticity, essential for learning and

density oxidized lipoprotein (oxLDL), which may

neuron survival, neuronal gene expression, and neurogenesis in the adult subventricular zone

complexes that block APP toxicity [28, 30, 31].

deposition sites, where these cells can phagocyte

Maintains microglial function in synaptic support and performs IL-1β dependent cognitive

APP gene promoter activity [16].

Cerebral cortex Stimulates physiological mechanisms of APP

[17, 18, 21].

memory [22, 23].

Cerebral cortex Regulates the cholesterol homeostasis and

**116**


#### **Table 1.**

*Alzheimer's disease associated receptors.*

This suggests that these receptors participate in several long-term changes in the nervous system (long-term plasticity) [60].

Finally, most of the receptors involved in AD (67%) are associated with beneficial effects on the disease. These receptors include nuclear receptors, such as VDR, membrane receptors, such as TLR5, and cytoplasmic receptors, such as GABAR. Most of the AD-associated receptors are found in the membrane of nerve cells (61%). Among the neuroprotective receptors, we can highlight the vitamin D receptor, responsible for vitamin D actions. Vitamin D is increasingly recognized as a substance involved in neuronal survival, taking part in psychiatric and

#### **Figure 1.**

*Proteins associated with AD. Proteins related to AD are shown according to their protective (a) or pathological (b) effects in AD. The receptors located in the green boxes are associated with neuroprotective effects on AD. Receptors located in red boxes are associated with AD pathophysiology. Proteins are shown according to their location in the cell (nucleus, membrane, intracellular or extracellular). Arrows/triangles represent activation, induction or increase. Inverted bars/triangles represent inhibition, deficit or decrease. Protein associated to AD protection are related to proteins involved in AD pathophysiological process. Two triangles represent overactivation. Elements in the figure are not showed in real scale. ROS, reactive oxygen.*

neurodegenerative diseases such as AD. The participation of vitamin D in neuronal survival may be related to its role in inhibiting the cellular oxidative stress and APP synthesis. Therefore, supplementation with vitamin D can help in the current AD treatment [61]. A beneficial role in inflammation, played by some receptors acting on inflammatory pathways, such as TLRs, has also been shown to be beneficial in the AD treatment [62]. More and more new treatments are being researched for AD, but unfortunately, the improvements have not been significant. What has been sought are combinations of treatments, which can result in some side effects in the elderly patient. Besides, current treatments are only symptomatic, that is, they do not modify the AD stage. These are cholinesterase inhibitors, used in all AD stages as they result in some beneficial effects on cognition and behavior. However, therapies affecting the AD stage are still under development. Therefore, efficient research must be conducted in this direction, instead of alleviating only the symptoms. Immunotherapy, for example, can be a viable option soon [63].
