Amylin Receptor: A Potential Therapeutic Target for Alzheimer’s Disease

Accumulation of amyloid beta protein in the brain is considered an early and seminal event in AD pathogenesis. Current treatment strategies for AD have focused on the inhibition of this protein and/or increasing its clearance from the brain. The amylin receptor has been identified as a target for the expression of deleterious effects of Aβ. Amylin receptor-based compounds have been shown to improve memory and learning in in vitro and in vivo transgenic mouse models of AD. The presence of amylin receptors on three critical cell types implicated in AD pathogenesis – neurons, microglia, and endothelial cells of the brain vasculature – is shedding new light on the contributions of this receptor to AD. Drugs that improve cognitive and pathological deficits in preclinical models of AD could serve as a novel platform in developing future disease-modifying therapies for AD and potentially for other neurodegenerative diseases. Alzheimer'sdisease (AD) is a progressive neurodegenerative disorder, characterized by senile plaques constituting extracellular deposits of β-amyloid (Aβ) fibrils. Since Aβ accumulation in the brain is considered an early event preceding, by decades, cognitive dysfunction, disease-modifying treatments are aimed at facilitating clearance of this protein from the brain or ameliorating its toxic effects. Recent studies have identified the amylin receptor as a capable mediator of the deleterious actions of Aβ and furthermore, administration of amylin receptor-based peptides has been shown to improve spatial memory and learning in transgenic mouse models of AD. Here, by discussing available evidence, we posit that the amylin receptor could be considered a potential therapeutic target for AD, and present the rationale for using amylin receptor antagonists to treat this debilitating condition. Alzheimer'sdisease (AD) is a progressive neurodegenerative disorder, characterized by senile plaques constituting extracellular deposits of β-amyloid (Aβ) fibrils. Since Aβ accumulation in the brain is considered an early event preceding, by decades, cognitive dysfunction, disease-modifying treatments are aimed at facilitating clearance of this protein from the brain or ameliorating its toxic effects. Recent studies have identified the amylin receptor as a capable mediator of the deleterious actions of Aβ and furthermore, administration of amylin receptor-based peptides has been shown to improve spatial memory and learning in transgenic mouse models of AD. Here, by discussing available evidence, we posit that the amylin receptor could be considered a potential therapeutic target for AD, and present the rationale for using amylin receptor antagonists to treat this debilitating condition. a key regulatory enzyme converting ATP to cyclic AMP, which serves as a second messenger, and is a critical molecule in eukaryotic signal transduction. indirectly influences the effects of an agonist or inverse agonist of a receptor at a site distinct from that of the orthosteric agonist binding site and induces a conformational change within the protein structure. amylin, or islet amyloid polypeptide, is a 37-residue peptide hormone that is cosecreted with insulin from the pancreatic β cells. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety. Human amylin is an amyloidogenic protein that shares physiochemical properties with β-amyloid protein. amylin receptor is a Class B GPCR composed of heterodimers of CTR and RAMPs. Dimers of CTR and either RAMP1, RAMP2, or RAMP3 comprise three amylin receptor subtypes, AMY1, AMY2, AMY3. amyloid plaques are aggregates of misfolded proteins, which stick together to form fibrous deposits in plaque form around cells and can disrupt the healthy function of neural elements. GPCR ligands selectively confer activity in one pathway over another, which triggers multidimensionality of GPCR signaling, also referred to functional selectivity. a highly selective semipermeable membrane barrier formed by endothelial cells (formed tight junctions) and astrocyte cell projections, allowing the passive diffusion of water, some gases, and lipid-soluble molecules, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function. regulate a wide range of endocrine and neuroendocrine functions and are endogenously stimulated by moderately large peptide hormones. a decline in global deterioration of intellectual function that may be severe enough to interfere with daily life. AD is the most common form of dementia and accounts for 60–80% percent of cases. metabolic disorder of multiple etiology characterized by chronic hyperglycemia with metabolic disturbances in the use of energy from food, resulting from defects in insulin secretion, insulin action, or both. a transfer process for GPCR protein from the endoplasmic reticulum to the Golgi apparatus and surface membrane. membrane-associated 'G protein' containing alpha (α), beta (β), and gamma (γ) subunits that mediate GPCR activation, catalyzing GTP–GDP exchange on the G-protein α-subunit. a lipid bilayer model assembled in vitro, as opposed to the bilayers in natural cell membranes or subcellular structures, and can be made with either synthetic or natural lipids. persistent increase in synaptic strength following high-frequency stimulation of synapses, regarded as one of the major cellular mechanisms underlying learning and memory. protein folded into an incorrect three-dimensional shape (unusual or incorrect tertiary structure), typically nonfunctional and often resistant to breakdown. Many proteins can be misfolded and trigger different pathologies. short segments of three-dimensional protein structure, spatially close but not necessarily adjacent in the sequence. Structural motifs may be conserved in a large number of different proteins. also called senile plaques, these are extracellular deposits of amyloid beta in the brain; the degenerative neural structures are often associated with an abundance of microglia and astrocytes. aggregates of hyperphosphorylated tau protein found in numerous tauopathies; constitute a primary pathological feature of AD. a feature of Type 2 diabetes in humans with deposition of amyloid in pancreatic islets containing amylin fibrils. long-term degenerative disorder of the CNS; affects the motor system with shaking, rigidity, slowness of movement, and difficulty walking. characterized by a histopathological presence of specific misfolded protein(s) deposits with common structural features and found in multiple organs, such as Alzheimer disease, Parkinson's disease, Type 2 diabetes. a major microtubule-associated protein, which abundant in neurons and expressed in low levels in astrocytes and oligodendrocytes. Abnormal hyperphosphorylation in neurons results in the presence of neurofibrillary tangles in AD. an AD transgenic mouse of overexpressed mutant human amyloid precursor protein (APP) containing human APP695 and mutated with KM670/671NL and V717F under the control of the hamster prion (PrP) gene promoter; this model shows age-related amyloid deposition, progressing with cognitive impairment as early as 3 months of age. transient receptor potential cation channel subfamily V member 4, a Ca2+-permeable, nonselective cation channel; functions in the regulation of systemic osmotic pressure. the most common form of diabetes; long-term metabolic disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. a protein fragment containing 36–43 amino acids and derived from cleavage of its precursor protein, amyloid precursor protein (APP), by the actions of β- and γ-secretase enzymes. It can aggregate to form oligomers and fibrils, thus giving rise to amyloid plaques, which are a pathological hallmark of AD pathology. a common motif of regular secondary protein structure in which two or more β strands are connected parallelly or antiparallelly by hydrogen bonds, forming a generally twisted, pleated sheet.