Amylin Receptor: A Potential Therapeutic Target for Alzheimer's Disease.

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.

Fu W ，Patel A ，Kimura R ，Soudy R ，Jhamandas JH ... -  《-》

β-Amyloid protein (Aβ) and human amylin regulation of apoptotic genes occurs through the amylin receptor.

Jhamandas JH ，Mactavish D 《-》

Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation.

Fu W ，Vukojevic V ，Patel A ，Soudy R ，MacTavish D ，Westaway D ，Kaur K ，Goncharuk V ，Jhamandas J ... -  《Journal of Neuroinflammation》

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.

Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aβ in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aβ and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Aβ. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by Aβ. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.

Zhu H ，Xue X ，Wang E ，Wallack M ，Na H ，Hooker JM ，Kowall N ，Tao Q ，Stein TD ，Wolozin B ，Qiu WQ ... -  《-》

Actions of β-amyloid protein on human neurons are expressed through the amylin receptor.

Disruption of neurotoxic effects of amyloid β protein (Aβ) is one of the major, but as yet elusive, goals in the treatment of Alzheimer's disease (AD). The amylin receptor, activated by a pancreatic polypeptide isolated from diabetic patients, is a putative target for the actions of Aβ in the brain. Here we show that in primary cultures of human fetal neurons (HFNs), AC253, an amylin receptor antagonist, blocks electrophysiological effects of Aβ. Pharmacological blockade of the amylin receptor or its down-regulation using siRNA in HFNs confers neuroprotection against oligomeric Aβ-induced caspase-dependent and caspase-independent apoptotic cell death. In transgenic mice (TgCRND8) that overexpress amyloid precursor protein, amylin receptor is up-regulated in specific brain regions that also demonstrate an elevated amyloid burden. The expression of Aβ actions through the amylin receptor in human neurons and temporospatial interrelationship of Aβ and the amylin receptor in an in vivo model of AD together provide a persuasive rationale for this receptor as a novel therapeutic target in the treatment of AD.

Jhamandas JH ，Li Z ，Westaway D ，Yang J ，Jassar S ，MacTavish D ... -  《-》