**2. Alzheimer's disease-associated receptors**

## **2.1 Nicotinic acetylcholine receptor**

Nicotinic acetylcholine receptors (nAChR) are involved with neuroprotective effects in AD. Furthermore, nAChR agonists and antagonists have been shown to have positive effects on memory. Cotinine and methyl cyclonite are examples of nAChR ligands associated with brain protection when in vitro and in vivo tests

have been performed. In addition, nAChR and the muscarinic acetylcholine receptor family (mAChR) are acetylcholine targets in the brain. The nAChR family is affected in AD because beta-amyloid peptides (Aβ) can interact with these receptors [1]. Acetylcholine (Ach) plays a crucial role in CNS. Choline acetyltransferase enzyme is responsible for ACh synthesis from acetyl-CoA and choline in the cytoplasm. The acetylcholine vesicular transporter absorbs the neurotransmitter in synaptic vesicles. After depolarization, ACh undergoes exocytosis in reaching the synaptic cleft, where it can bind with its receptors. The ACh in the synaptic cleft is readily hydrolyzed by the acetylcholinesterase enzyme, forming acetate and choline, which is recycled at the presynaptic nerve terminal by the high-affinity choline transporter. Cholinergic neurons located in the basal forebrain, including the neurons which form Meynert's basal nucleus, are severely affected in AD. The loss of cholinergic neurons contributes to memory and attention deficits. Therefore, drugs acting on the cholinergic system represent a promising option for treating AD patients [2]. The conventional therapeutic prescription for AD consists of three acetylcholinesterase inhibitors and one NMDA receptor antagonist. Researchers around the world are developing new nAChR agonists to develop drugs with lower risks and adverse effects [3].

### **2.2 Estrogen receptor**

Another important target in AD is the estrogen receptor (ER), which may represent a promising therapeutic approach since its activation through agonists prolongs survival, improves spatial recognition memory, and decreases the amyloid pathology progression in animal models of AD. On the other hand, estrogen receptor genetic polymorphisms have been associated with cognitive impairment, accelerated brain aging, and increased risk of AD, predominantly in women. A methylation promoter in estrogen receptor α is also related to impaired cognitive function and quality of life in AD patients by inhibiting ERα mRNA expression and transcription [4]. Estrogen can increase neural plasticity, cognitive functions, and the brain's regenerative potential. The beneficial effects of estrogen on neural plasticity occur at three levels: cellular, morphological, and synaptic function. Studies have shown that estradiol can increase neurogenesis in several brain regions, such as the hippocampal gyrus. These estrogen-induced hippocampal neurons contribute to learning and memory. Estradiol can also rapidly increase the number of dendritic spines in the hippocampus, amygdala, and hypothalamus and thus improve the performance in a hippocampal-dependent memory task. Moreover, estradiol is an effective enhancer of synaptic transmission in the hippocampal system. Estradiol plays an important role in promoting neurogenesis and neuronal plasticity to maintain healthy cognitive function and protect against women's cognitive decline during aging [5]. Therefore, estrogen with selective effects on ERα or G proteincoupled estrogen receptors (GPER1 or GqMER) can be used to influence the inflammation process resolution, with positive effects on AD progression [6].

#### **2.3 Ryanodine receptor**

Ryanodine receptors (RyR) are an ion channel family responsible for calcium release from intracellular reserves during muscle contraction. Calcium homeostasis is known to be related to cognition; thus, RyR may be associated with AD, especially RyR 3, which is found in various nervous system areas. In addition, RyR 1 and RyR 2 are also found in the brain, although they are not predominantly present in the nervous system. Ryanodine receptors can be regulated by several proteins and ions, as well as redox modifications. Antioxidants importantly prevent cognitive decline,

**107**

*Alzheimer's Disease Neuroprotection: Associated Receptors*

tion. Dantrolene, a RyR inhibitor, may be an AD treatment [9].

age-dependent impairment in GABAergic interneurons [12].

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

**2.5 Receptor for advanced glycation end products**

**2.4 Gamma-Aminobutyric Acid receptor**

long-term depolarization, and memory loss by inhibiting RyR sensitization [7]. Calcium-dependent signaling pathways are related to AD pathogenesis. A pharmacological approach (using a RyR stabilizing drug) or gene therapy of calcium leakage (mediated by RyR2) improved synaptic plasticity, and behavioral and cognitive functions and reduced Aβ loading. Genetically, altered mice (congenital leaking of RyR2) exhibited premature and severe defects in synaptic plasticity, and behavioral and cognitive function. These data provide an underlying mechanism for RyR2 channels, which can be considered as possible therapeutic targets in AD [8]. Additionally, calcium accumulation may result in the calpain and CaMKK2 activation, contributing to Aβ production and tau phosphorylation. Ryanodine receptor dysfunction can also lead to abnormal activation and accumulation of PKR kinase in AD brains. PKR kinase is linked to calcium accumulation and PKR autophosphorylation can be triggered by Aβ peptides in neuronal cultures in a calcium-dependent manner. In turn, PKR activation may lead to Aβ production by regulating BACE1 levels and abnormal tau protein phosphorylation by GSK3 activa-

Gamma-Aminobutyric Acid receptor (GABAR) inhibition is also related to a better prognosis in AD. Gamma-Aminobutyric Acid receptor regulates learning, memory, and cognition, inhibits Adenylyl Cyclase and the cAMP cascade, as well as controls GABA and glutamate release. CGP35348 is a GABA receptor antagonist, and the CGP35348 hippocampal concentration is a crucial point for improving memory by reducing APP toxicity. Several neurological and psychiatric disorders occur with neuronal hyperexcitability in specific regions of the brain or spinal cord, partly due to some loss and/or dysfunction of GABAergic inhibitory interneurons [10]. Strategies which improve inhibitory neurotransmission in the affected brain regions may decrease deficits associated with these disorders. This perception has prompted an interest in testing the efficacy of GABAergic interneuron grafting in the brain or spinal cord regions which exhibit hyperexcitability, GABAergic interneurons scarcity, or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders [10]. Defective GABAergic neuronal functions can lead to cortical network hyperactivity and aberrant neuronal oscillations and thereby generate a detrimental change in memory processes [11]. In this context, GABAergic cell therapy may decrease neurological deficits in AD preclinical models [10]. Alzheimer patients have low GABA levels in the brain and spinal cerebrospinal fluid (SCF), and these changes are more severe in ApoE4 allele carriers. ApoE4 is associated with increased brain activity at rest and memory tasks, possibly reflecting impaired GABAergic inhibitory control. In addition, GABA levels in human SCF change with aging, constituting the strongest AD risk factor. Therefore, ApoE4 may at least partially contribute to the AD pathogenesis, causing

*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*

risks and adverse effects [3].

**2.2 Estrogen receptor**

**2.3 Ryanodine receptor**

have been performed. In addition, nAChR and the muscarinic acetylcholine receptor family (mAChR) are acetylcholine targets in the brain. The nAChR family is affected in AD because beta-amyloid peptides (Aβ) can interact with these receptors [1]. Acetylcholine (Ach) plays a crucial role in CNS. Choline acetyltransferase enzyme is responsible for ACh synthesis from acetyl-CoA and choline in the cytoplasm. The acetylcholine vesicular transporter absorbs the neurotransmitter in synaptic vesicles. After depolarization, ACh undergoes exocytosis in reaching the synaptic cleft, where it can bind with its receptors. The ACh in the synaptic cleft is readily hydrolyzed by the acetylcholinesterase enzyme, forming acetate and choline, which is recycled at the presynaptic nerve terminal by the high-affinity choline transporter. Cholinergic neurons located in the basal forebrain, including the neurons which form Meynert's basal nucleus, are severely affected in AD. The loss of cholinergic neurons contributes to memory and attention deficits. Therefore, drugs acting on the cholinergic system represent a promising option for treating AD patients [2]. The conventional therapeutic prescription for AD consists of three acetylcholinesterase inhibitors and one NMDA receptor antagonist. Researchers around the world are developing new nAChR agonists to develop drugs with lower

Another important target in AD is the estrogen receptor (ER), which may represent a promising therapeutic approach since its activation through agonists prolongs survival, improves spatial recognition memory, and decreases the amyloid pathology progression in animal models of AD. On the other hand, estrogen receptor genetic polymorphisms have been associated with cognitive impairment, accelerated brain aging, and increased risk of AD, predominantly in women. A methylation promoter in estrogen receptor α is also related to impaired cognitive function and quality of life in AD patients by inhibiting ERα mRNA expression and transcription [4]. Estrogen can increase neural plasticity, cognitive functions, and the brain's regenerative potential. The beneficial effects of estrogen on neural plasticity occur at three levels: cellular, morphological, and synaptic function. Studies have shown that estradiol can increase neurogenesis in several brain regions, such as the hippocampal gyrus. These estrogen-induced hippocampal neurons contribute to learning and memory. Estradiol can also rapidly increase the number of dendritic spines in the hippocampus, amygdala, and hypothalamus and thus improve the performance in a hippocampal-dependent memory task. Moreover, estradiol is an effective enhancer of synaptic transmission in the hippocampal system. Estradiol plays an important role in promoting neurogenesis and neuronal plasticity to maintain healthy cognitive function and protect against women's cognitive decline during aging [5]. Therefore, estrogen with selective effects on ERα or G proteincoupled estrogen receptors (GPER1 or GqMER) can be used to influence the inflam-

mation process resolution, with positive effects on AD progression [6].

Ryanodine receptors (RyR) are an ion channel family responsible for calcium release from intracellular reserves during muscle contraction. Calcium homeostasis is known to be related to cognition; thus, RyR may be associated with AD, especially RyR 3, which is found in various nervous system areas. In addition, RyR 1 and RyR 2 are also found in the brain, although they are not predominantly present in the nervous system. Ryanodine receptors can be regulated by several proteins and ions, as well as redox modifications. Antioxidants importantly prevent cognitive decline,

**106**

long-term depolarization, and memory loss by inhibiting RyR sensitization [7]. Calcium-dependent signaling pathways are related to AD pathogenesis. A pharmacological approach (using a RyR stabilizing drug) or gene therapy of calcium leakage (mediated by RyR2) improved synaptic plasticity, and behavioral and cognitive functions and reduced Aβ loading. Genetically, altered mice (congenital leaking of RyR2) exhibited premature and severe defects in synaptic plasticity, and behavioral and cognitive function. These data provide an underlying mechanism for RyR2 channels, which can be considered as possible therapeutic targets in AD [8]. Additionally, calcium accumulation may result in the calpain and CaMKK2 activation, contributing to Aβ production and tau phosphorylation. Ryanodine receptor dysfunction can also lead to abnormal activation and accumulation of PKR kinase in AD brains. PKR kinase is linked to calcium accumulation and PKR autophosphorylation can be triggered by Aβ peptides in neuronal cultures in a calcium-dependent manner. In turn, PKR activation may lead to Aβ production by regulating BACE1 levels and abnormal tau protein phosphorylation by GSK3 activation. Dantrolene, a RyR inhibitor, may be an AD treatment [9].
