**2.5 Receptor for advanced glycation end products**

The relationship between the receptor for advanced glycation end products (RAGE) and AD has also recently been established; RAGE is widely expressed and regulated in the AD brain. Furthermore, RAGE is involved with the transport of beta-amyloid protein through the blood-brain barrier (BBB) to the brain parenchyma. Interactions between RAGE and APP result in inflammatory responses and oxidative stress, as well as reduce cerebral blood flow. The receptor also inhibits the elimination of APP and RAGE ligands such as AGE, HMGB1, and S100β, which are 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 cells expressing RAGE in vitro, as well as in the brains of mice [14].

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 potential in retarding AD progression [15].

#### **2.6 Vitamin D receptor**

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 cells [16].

Third, VD can stimulate macrophages, which increases amyloid plaque clearance. 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

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*Alzheimer's Disease Neuroprotection: Associated Receptors*

acetylcholine, dopamine, serotonin, and aminobutyric gamma acid. Finally, VD also reduces Aβ-induced cytotoxicity and apoptosis in primary cortical neurons. A recent study found that Aβ induction of nitric oxide synthase, part of the AD inflammatory process, depends on the VDR pathway disruption. VD supplementation improves age-related cognitive decline, learning, and memory in older rats. A cross-sectional study found that VD deficiency was associated with increased white matter volume and reduced gray matter volume. In summary, low VD concentrations may increase the risk of dementia and AD through vascular and neurodegen-

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

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

astrocytes, which are activated in AD [21].

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

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

erative mechanisms [16].

**2.7 Retinoid X receptor**

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

acetylcholine, dopamine, serotonin, and aminobutyric gamma acid. Finally, VD also reduces Aβ-induced cytotoxicity and apoptosis in primary cortical neurons. A recent study found that Aβ induction of nitric oxide synthase, part of the AD inflammatory process, depends on the VDR pathway disruption. VD supplementation improves age-related cognitive decline, learning, and memory in older rats. A cross-sectional study found that VD deficiency was associated with increased white matter volume and reduced gray matter volume. In summary, low VD concentrations may increase the risk of dementia and AD through vascular and neurodegenerative mechanisms [16].
