**2.7 Retinoid X receptor**

*Neuroprotection - New Approaches and Prospects*

potential in retarding AD progression [15].

**2.6 Vitamin D receptor**

involved in the neurodegenerative disease progression. Additionally, RAGE/AGE interactions induce the apoptosis cascade and neuronal inflammation [7]. In addition, RAGE has been considered as a therapeutic approach in AD; in fact, a RAGE antagonist demonstrated a protective effect in an animal model. Chronic oral dosing of PF-04494700 antagonist in transgenic AD mice reduced Aβ levels, improved performance in spatial memory testing, and normalized the electrophysiological recordings of hippocampal slices. According to the results of the Phase II clinical study [13], the RAGE inhibitor has an excellent safety profile and is well-tolerated for over 10 weeks in patients with oral AD. These inhibitors block the binding of Aβ peptides to the RAGE V domain as well as inhibit the cell stress induced by Aβ in

Moreover, a RAGE inhibitor (FPS-ZM1) has no animal toxic activity and easily crosses the BBB. In aged mice with AD, FPS-ZM1 can inhibit the RAGE-mediated influx of Aβ40 and Aβ42 in the brain. FPS-ZM1 binds exclusively to RAGE in the brain, inhibiting Aβ production and suppressing microglia activation and neuroinflammatory response. Blocking RAGE actions in the SCF and brain normalizes cognitive performance and cerebral blood flow. FPS-ZM1 is a potent RAGE blocker, thereby controlling the progression of Aβ-mediated brain disorder [14]. Furthermore, metabolic syndrome is a risk factor for cognitive decline in AD, and RAGE has been associated with metabolic syndrome, as this receptor directly contributes to an inflammatory process and oxidative stress. Thus, the RAGE inhibition is able to reduce cellular toxicity, and therefore, RAGE inhibitors have therapeutic

Vitamin D (VD) acts through the vitamin D receptor (VDR), expressed in various tissues, including the nervous system. Vitamin D receptor is related to memory and cognitive functions. Research has reported a higher prevalence of VD deficiency in AD patients and individuals with VD deficiency had twice the risk of developing AD compared with individuals with sufficient VD concentrations. Several potential mechanisms which link low VD levels to the risk of dementia have been identified. First, VDR is expressed throughout the brain, including areas involved in memory, such as the hippocampus. The enzyme which synthesizes the active form of VD, 1α-hydroxylase, is also produced in various brain areas. Second, the VD active form (1,25dihydroxyvitamin D3 or 1,25-D3) regulates neurotrophin expression, such as neurotrophin 3, Glial cell-derived neurotrophic factor (GDNF) and neural growth factor (NGF). NGF has been implicated in maintaining and regulating the normal function of the septohippocampal pathway, which is involved

in learning and memory. In addition, NGF levels are substantially reduced in AD patients and NGF negatively modulates APP protein gene expression, while increased APP expression is observed after NGF suppression. Furthermore, VD analogs increase APP binding to the NGF promoter, inducing NGF expression. Therefore, 1,25-D3 contributes to the development, survival, and function of neural

Third, VD can stimulate macrophages, which increases amyloid plaque clear-

ance. Fourth, the antioxidant effect of VD may be related to the modulation of antioxidant gene expression. Oxidative stress is known to contribute to the pathophysiology of neurodegenerative diseases, which leads to impaired cognitive and behavioral function. Genetic analyses of the human genome have pointed to several genes playing a role in susceptibility to AD, such as genes which are involved in inflammation and oxidative stress [7]. Fifth, VD also plays a role in vascular protection. Sixth, VD regulates neurotransmitter metabolism in the CNS, such as

cells expressing RAGE in vitro, as well as in the brains of mice [14].

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cells [16].

Vitamin D receptor interacts with the retinoid receptor X (RXR) to perform VD actions. Retinoid receptor X activation can stimulate the normal physiological processes by which APP is eliminated from the brain. Thus, RXR agonists may be useful in treating AD. Two-week treatment with an RXR agonist (bexarotene) in an AD animal model resulted in clearance of intraneuronal amyloid deposits. Additionally, treatment with bexarotene improved remote memory stabilization in fear-conditioned mice and improved olfactory habituation. In addition, bexarotene pretreatment improved neuronal survival in response to glutamate-induced excitotoxicity. The bexarotene effects were accompanied by reduced amyloid plaque levels, decreased astrogliosis and suppression of inflammatory gene expression. Therefore, treatment with RXR agonists can decrease neuron loss, reverse cognitive deficits, and improve neural circuit function in aggressive AD models [17]. Retinoid receptor X agonists can increase the expression of ApoE, ABCA1, and ABCG1 by activating RXR heterodimers. On the other hand, these beneficial effects are blocked by the RXR antagonist, which can accentuate cellular oxidative stress [18].

Interestingly, RXR decreased expression was identified in the AD mouse model and in cells treated with Aβ peptides [19]. However, the action mechanism of RXR ligands remains unknown, particularly in the context of human ApoE [20]. Retinoids have effects on various physiological and pathological processes in the brain. For example, retinoic acid (RA) signaling is widely detected in the adult CNS, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are mainly involved in neural patterns, axon differentiation, and cell growth. Retinoids also play a key role in preserving the differentiated state of adult neurons. Impaired RA signaling may result in neurodegeneration and AD progression. Recent studies have shown severe deficiencies in mouse learning and memory during RA deprivation, indicating its importance in preserving memory. Defective cholinergic neurotransmission is related to cognitive deficits in AD. Retinoic acid is also known to increase choline acetyltransferase expression and the activity in neuronal cell lines. In addition, retinoids have been shown to inhibit the expression of proinflammatory chemokines and cytokines in microglia and astrocytes, which are activated in AD [21].

#### **2.8 N-methyl-d-aspartate receptors**

N-methyl-d-aspartate receptors (NMDAR) participate in CNS development and are involved in synaptic plasticity, which is essential for learning and memory. Cognitive symptoms associated with learning and memory deficits have been associated with glutaminergic neurotransmission disorders. Excitatory glutaminergic neurotransmission via NMDAR is critical for synaptic plasticity and neuron survival. However, excessive neuron stimulation by the glutamate neurotransmitter causes cytotoxicity and results in neuronal damage and death, underlying a

potential mechanism of neurodegeneration in AD. Therefore, blocking NMDAR receptor-mediated glutaminergic neurotransmission can decrease cytotoxicity, thereby preventing further damage to neurons and cellular oxidative damage [22]. Therefore, NMDAR antagonists have emerged as potential compounds for AD patients since the receptor itself has many subunits and its variants have several brain functions. For example, conantokine acts as an NMDA receptor antagonist and plays an important role in understanding the importance of NMDA receptor inhibition in the AD treatment. Moreover, NMDAR activation might be blocked by an AD drug, memantine, an NMDAR antagonist which selectively blocks the function of extra synaptic NMDARs, but does not affect normal neurotransmission. However, memantine (and other current medications used to treat AD) only relieve the symptoms and do not alter the disease progression [23].

#### **2.9 Cholesterol receptors**

Regarding cholesterol receptors, some specific genotypes have been related to a higher or lower risk of dementia and AD. Even genotypes associated with AD neuropathology attenuation could be associated with late-onset of dementia. Liver nuclear X receptors (LXRs) are the main regulators of cholesterol homeostasis and CNS inflammation. The brain, which contains about 25% of total body cholesterol, requires a complex and balanced cholesterol metabolism to maintain neuronal function. Deregulation of cholesterol metabolism has been implicated in several neurodegenerative diseases, including AD. Due to their anti-inflammatory activities, LXRs play a crucial role in CNS function. Although LXR agonists have therapeutic potential in neurological diseases, the use of LXR in these pathologies remains problematic. The recent discovery of cholesterol derivatives which function as LXR agonists has shown new roles for LXRs in midbrain neurogenesis. Elucidating the repertoire of endogenous ligands for LXR will improve the understanding of how this receptor regulates CNS lipid metabolism [24].

Nuclear X receptor signaling affects AD development through various pathways. Studies indicate that LXR genetic loss in transgenic mice results in increased amyloid plaques. Studies also suggest that LXRs activation in mice improves the expression of cholesterol efflux-linked genes (ApoE and ABCA-1), induces APP processing, and reduces Aß synthesis, with significant improvement in memory. Furthermore, LXR agonists have also been shown to inhibit neuroinflammation by modulating microglial phagocytosis and repressing COX2, MCP1, and INOS expression in glial cells [25]. The T allele of NR1H2 (rs2695121) presents the most significant risk for AD among all LXR-β gene polymorphisms. Taken together, these findings suggest that brain-penetrable LXR agonists or LXR modulators may be useful therapeutic agents for AD treatment and prevention [26].

Additionally, chromosome 12p has been recognized as an AD-associated region. This chromosome includes genes for LDL receptor 1 (LRP1) and oxidized lowdensity lipoprotein receptor 1 (OLR1). OLR1 is a class E scavenger receptor and is a transmembrane glycoprotein. In vitro factors such as oxidized LDL, oxidative stress, and inflammatory cytokines, as well as in vivo factors such as diabetes mellitus, hyperlipidemia, and hypertension, may induce OLR1 expression. Increased oxidized LDL levels induce endothelial cell activation and dysfunction, apoptosis, and impaired vessel relaxation, thus contributing to atherosclerosis development and progression through OLR1. Epidemiological and clinical literature has reported an association between atherosclerosis, vascular risk factors, and AD. Therefore, ORL1 variations may lead to low efficiency in the oxidized LDL removal and therefore increased Aβ levels, which may result in neuronal death. Indeed, a single nucleotide polymorphism in OLR1 located in the 3′ untranslated region of the gene

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*Alzheimer's Disease Neuroprotection: Associated Receptors*

may influence regulatory microRNA binding and OLR1 homeostasis. Several stud-

Toll-like receptors (TLRs) are innate immune system receptors which are activated by pathogens (PAMP) or damage-associated molecular patterns (DAMPs). Toll-like receptors are associated with neuronal injury in chronic inflammatory conditions but also with functional recovery after nerve injury. Amyloid aggregates seem to be a type of DAMP and may interact and activate standard recognition receptors. Two TLR actions (ligand binding and immune signaling) may have beneficial effects on AD pathology. Moreover, microglial activation represents an important AD hallmark. Analysis of genetic polymorphisms suggested relationships between TLR polymorphisms and AD risk, further supporting the hypothesis that TLRs are involved in AD [28]. In fact, TLR2 is elevated in the hippocampus and cortex of AD patients and mice. In this context, it was observed that a TLR2 binding peptide (WT TIDM) inhibited Aβ-induced microglial activation, reduced Aβ load, attenuated neuronal apoptosis, and improved memory and learning in mice. However, WT TIDM peptide was not effective in TLR2 knockout mice [29]. Importantly, TLR5 binds to APP with high-affinity, forming complexes which block APP toxicity. In turn, APP fibrils modulate the human TLR5 activation via flagellin, but APP cannot activate TLR5 signaling by themselves. Thus, TLR5-related biological data suggest this receptor as a potential agent in AD therapy [30]. A new TLR9 signaling pathway has recently been associated with the immune-inflammatory response, reducing Aβ levels in AD mice. Therefore, TLR9 may represent a functional candidate gene for AD [31]. Moreover, TLR4 has also been described in the brain and seems to regulate some physiological processes such as neurogenesis. In this sense, TLR4 plays an important role during neurodegenerative disorders. PRDX6 has been shown to inhibit neural stem cell neurogenesis by down-regulating the TLR4 signaling pathway [32]. An early TLR3-mediated signal improves Aβ neuronal autophagy, although it increases neuronal apoptosis in the late stage of AD. Similarly, TLR7, TLR8, and TLR9 may improve early Aβ microglial uptake, but over time, they contribute to neuroinflammation. Therefore, TLRs, in particular TLR2 and TLR4, represent suitable targets for therapeutic intervention in AD and carefully targeting them may increase Aβ autophagy and phagocytosis, as well as reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could produce a

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

ies have reported an association between this variant and AD [27].

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

therapeutic benefit in AD patients [33].

**2.11 Chemokine receptors**

**2.10 Toll-like receptors**

may influence regulatory microRNA binding and OLR1 homeostasis. Several studies have reported an association between this variant and AD [27].
