**2.11 Chemokine receptors**

Another molecule involved in AD is the chemokine receptor CX3C1 (CX3CR1), which performs IL-1β-dependent cognitive functions. It is known that CX3CR1 maintains microglial homeostasis and is essential for microglia function in synaptic support since it is highly expressed in microglia. In vivo, CX3CR1-GFP knock-in mice (in which GFP replaced a CX3CR1 allele) were used to study the role of microglia in AD and other brain diseases. Under physiological conditions, decreased CX3CR1 function affects cognitive functions in an IL-1β-dependent manner, as well as exacerbates LPS-induced inflammation, suggesting that CX3CR1 is essential for nerve synapses. In this context, CX3CL1/CX3CR1 axis dysregulation in AD may have neuroprotective and neurotoxic effects depending on the model used. It is also possible that CX3CR1 is involved in the death of neurons with intracellular TAU deposits and the subsequent TAU release [34]. Still, regarding chemokine

receptors, CCL2 receptor (CCR2) was also associated with AD since CCR2 promotes the recruitment of bone marrow monocytes into the APP deposition sites in the parenchyma, where APP phagocytosis occurs. In mice, CCR2 deficiency accelerated early AD progression, impairing mononuclear phagocyte accumulation. CCR2−/− mice exhibited high APP levels and low CD11b+ cell recruitment in the brain. Importantly, these mice had increased mortality in a dose-dependent manner of the CCR2 gene. Subsequent studies showed that APP reduction is due to the monocyte accumulation in the perivascular spaces and possibly its infiltration into the brain parenchyma. These findings were corroborated by the fact that CCR2 deficiency worsened memory and increased soluble APP levels in mice [34].

#### **2.12 Glucocorticoid receptors**

The main AD risk factor is aging, but there is growing evidence that chronic stress or stress-related disorders may increase the chance of developing AD. Thus, depressive disorder may be a risk factor for AD [35]. Stress promotes AD progression on neurons and glial cells, supporting an important pro-inflammatory role of glucocorticoid (GC) in the CNS [36]. Glucocorticoids act via two receptors: mineralocorticoid and glucocorticoid receptors (GR) and can participate in APP generation and APP activity in the brain. There is a cross-talk between APP and GRs in hippocampal excitatory synapses, which may contribute to abnormal brain activity during the AD pathogenesis. Both AD patients and AD mice have dysregulated hypothalamic-pituitary-adrenal (HPA) axis, marked by hypercortisolemia early in the AD pathology. Thus, in early AD, while APP levels slowly increase in the brain, GR activity is probably abnormally high [37]. Moreover, GRs hyperactivation induces brain changes similar to AD changes. In the brain, GCs are regulators of dendritic spine renewal and microglia activity, two strongly altered phenomena in AD. Although well established that GCs initiate the brain neuroinflammatory response, it is not known whether GRs modulate dendritic spine plasticity and microglial activity in AD [36].

Several strategies aiming GR has been tested to counteract HPA axis dysregulation and GC overproduction. Given the GR ubiquitous expression, antagonists have many side effects, limiting the GR therapeutic potential. However, a new class of selective molecules has been developed, acting as GR modulators. They selectively reduce GR-dependent pathogenic processes while retaining the beneficial aspects of GR signaling. Indeed, these "selective GR modulators" induce receptor conformations that allow the activation of only a subset of downstream signaling pathways, explaining their ability to combine agonistic and antagonistic properties. Therefore, targeting GR with selective modulators, alone or in association with current strategies, is attractive to develop new strategies aiming disorders associated with HPA axis dysregulation [35]. Dexamethasone, a GR agonist, was able to reduce the dendritic spine density, induced the microglia proliferation, and activated the microglia in the mouse hippocampus. Besides, in vitro microglial cells were activated by dexamethasone. In contrast, treatment with mifepristone, a GRs antagonist, strongly increased dendritic column density, decreased microglia density, and improved mice behavioral performance [36].

#### **2.13 G-protein-coupled receptor 40**

There are a large number of polyunsaturated fatty acids in the nervous system, such as docosahexaenoic acid (DHA), an omega 3 carboxylic acid. The DHA binds to G-protein-coupled receptor 40 (GPR40) and exerts protective effects on the nervous system. For example, GPR40 can increase synaptic plasticity, neuronal

**113**

*Alzheimer's Disease Neuroprotection: Associated Receptors*

activity, and inhibits neuronal apoptosis. In this context, GPR40 was considered a possible target in dementia [38]. The receptor is expressed in several brain areas, including the hippocampus, which is involved in learning and spatial memory. However, few studies are investigating the functional role of GPR40 in the brain [39]. One study evaluated the GPR40 functional role in the AD mouse model. Groups treated with GPR40 significantly improved cognitive performance and GPR40 agonist-treated groups improved learning and memory skills in various tests. Besides, GPR40 activation caused CREB phosphorylation and increased neurotrophic factors levels, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in hippocampal neurons. These results suggest that GPR40 can be a therapeutic candidate for neurogenesis and neuroprotection in AD treatment and prevention [39] since GPR40 agonists can promote adult neurogenesis, inhibit neuronal apoptosis,

and play a vital role in protecting nerves and decreasing brain damage [38].

The triggered receptor expressed in myeloid cells 2 (TREM2) is a soluble protein carried by macrophages through ventricles and choroid plexus, entering the brain parenchyma through radial glial cells. TREM2 is important for innate immunity, but it is also essential for neuroplasticity and myelination. During later stages of life, the TREM2 absence can accelerate aging processes, neuronal cell loss and reduce microglial activity, leading to neuroinflammation. Inflammation plays an important role in neurodegenerative diseases and TREM2 can be important to immunomodulation and neuroprotection [40]. As a member of the immunoglobulin superfamily, TREM2 can suppress inflammatory responses, mediates phagocytic pathways, is involved with neuronal survival and neurogenesis, as well as contributes to CNS neuroimmune homeostasis. Changes in TREM2 are involved in AD-related neuropathology, including Aβ deposition, tau hyperphosphorylation, neuroinflammation, and neuronal and synaptic losses in AD animal models. However, the precise underlying mechanisms about TREM2 have not yet been fully characterized [41]. Besides, TREM2 might be related to microglial activation, promoting the association of microglial cells with APP plaques. Therefore, microglia can decrease APP plaque growth, limiting APP toxicity. On the other hand, this phagocytotic capacity is impaired by TREM2 deficiency. Moreover, different mutations in TREM2 are associated with AD [42, 43]. Interestingly, recent findings also suggested that the association between TREM2 variants and the AD risk varies according to different

The serotoninergic neurotransmitter system has been implicated in AD pathogenesis. The 5-hydroxytryptamine 6 receptor (5HTR6) is expressed in brain areas involved with cognitive processes and has been investigated as a possible therapeutic target in AD symptomatology. Besides, 5HTR6 may be added to currently approved "Food and Drug Administration" therapies: cholinesterase inhibitors and NMDA receptor antagonists since 5HTR6 controls the pyramidal neurons' migration during corticogenesis. In addition, 5HTR6 is a TOR signaling activator and seems to regulate GABAergic, glutamatergic, and cholinergic activity. Therefore, 5HTR6 is involved in cognition, anxiety, memory, affective state, among others [44]. Several kinds of research have been conducted with selective 5HTR6 antagonists. These antagonists act by modulating the glutamate and GABA levels, consequently increasing dopamine, ACh, and norepinephrine concentrations in

**2.14 Triggered receptor expressed on myeloid cells 2**

ethnicities and populations [41].

**2.15 5-Hydroxytryptamine 6 receptor**

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

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

*Neuroprotection - New Approaches and Prospects*

**2.12 Glucocorticoid receptors**

microglial activity in AD [36].

improved mice behavioral performance [36].

**2.13 G-protein-coupled receptor 40**

receptors, CCL2 receptor (CCR2) was also associated with AD since CCR2 promotes the recruitment of bone marrow monocytes into the APP deposition sites in the parenchyma, where APP phagocytosis occurs. In mice, CCR2 deficiency accelerated early AD progression, impairing mononuclear phagocyte accumulation. CCR2−/− mice exhibited high APP levels and low CD11b+ cell recruitment in the brain. Importantly, these mice had increased mortality in a dose-dependent manner of the CCR2 gene. Subsequent studies showed that APP reduction is due to the monocyte accumulation in the perivascular spaces and possibly its infiltration into the brain parenchyma. These findings were corroborated by the fact that CCR2 deficiency

The main AD risk factor is aging, but there is growing evidence that chronic stress or stress-related disorders may increase the chance of developing AD. Thus, depressive disorder may be a risk factor for AD [35]. Stress promotes AD progression on neurons and glial cells, supporting an important pro-inflammatory role of glucocorticoid (GC) in the CNS [36]. Glucocorticoids act via two receptors: mineralocorticoid and glucocorticoid receptors (GR) and can participate in APP generation and APP activity in the brain. There is a cross-talk between APP and GRs in hippocampal excitatory synapses, which may contribute to abnormal brain activity during the AD pathogenesis. Both AD patients and AD mice have dysregulated hypothalamic-pituitary-adrenal (HPA) axis, marked by hypercortisolemia early in the AD pathology. Thus, in early AD, while APP levels slowly increase in the brain, GR activity is probably abnormally high [37]. Moreover, GRs hyperactivation induces brain changes similar to AD changes. In the brain, GCs are regulators of dendritic spine renewal and microglia activity, two strongly altered phenomena in AD. Although well established that GCs initiate the brain neuroinflammatory response, it is not known whether GRs modulate dendritic spine plasticity and

Several strategies aiming GR has been tested to counteract HPA axis dysregulation and GC overproduction. Given the GR ubiquitous expression, antagonists have many side effects, limiting the GR therapeutic potential. However, a new class of selective molecules has been developed, acting as GR modulators. They selectively reduce GR-dependent pathogenic processes while retaining the beneficial aspects of GR signaling. Indeed, these "selective GR modulators" induce receptor conformations that allow the activation of only a subset of downstream signaling pathways, explaining their ability to combine agonistic and antagonistic properties. Therefore,

There are a large number of polyunsaturated fatty acids in the nervous system, such as docosahexaenoic acid (DHA), an omega 3 carboxylic acid. The DHA binds to G-protein-coupled receptor 40 (GPR40) and exerts protective effects on the nervous system. For example, GPR40 can increase synaptic plasticity, neuronal

targeting GR with selective modulators, alone or in association with current strategies, is attractive to develop new strategies aiming disorders associated with HPA axis dysregulation [35]. Dexamethasone, a GR agonist, was able to reduce the dendritic spine density, induced the microglia proliferation, and activated the microglia in the mouse hippocampus. Besides, in vitro microglial cells were activated by dexamethasone. In contrast, treatment with mifepristone, a GRs antagonist, strongly increased dendritic column density, decreased microglia density, and

worsened memory and increased soluble APP levels in mice [34].

**112**

activity, and inhibits neuronal apoptosis. In this context, GPR40 was considered a possible target in dementia [38]. The receptor is expressed in several brain areas, including the hippocampus, which is involved in learning and spatial memory. However, few studies are investigating the functional role of GPR40 in the brain [39]. One study evaluated the GPR40 functional role in the AD mouse model. Groups treated with GPR40 significantly improved cognitive performance and GPR40 agonist-treated groups improved learning and memory skills in various tests. Besides, GPR40 activation caused CREB phosphorylation and increased neurotrophic factors levels, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in hippocampal neurons. These results suggest that GPR40 can be a therapeutic candidate for neurogenesis and neuroprotection in AD treatment and prevention [39] since GPR40 agonists can promote adult neurogenesis, inhibit neuronal apoptosis, and play a vital role in protecting nerves and decreasing brain damage [38].
