Amylin Pharmacology in Alzheimer's Disease Pathogenesis and Treatment

Abstract

The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer's disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer's disease. The traditional "gain of toxic function" properties assigned to amyloid proteins are, however, contrasted by several reports highlighting neuroprotective effects of amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address the paradoxical nature of this hormone's signaling in the context of AD pathogenesis.

Keywords: Alzheimer’s disease; amylin; amyloid; diabetes; metabolism; neuroprotection; therapy.

Fig. (1)

The proposed signaling relationships between amylin, pramlintide (PRAM), and AMYR in AD as discussed throughout this review of the current literature. Top Left: Amylin aggregates (also mimicked by AMYR antagonist) may serve as a “loss of function hypothesis” of normal AMYR downstream signaling during Alzheimer’s disease (AD) or metabolic dysregulation by blocking the receptor. It is proposed that due to this loss of amylin, there will be toxic consequences such as increased A β pathology, Tau phosphorylation and disruption of cognitive processes. Top Right: Proposed therapeutic approach signaling of amylin, PRAM and amylin as monomers activating AMYR in the brain leads to downstream adenylate cyclase activation to increase ERK signaling that leads to increased neuroprotective effects. Bottom Left: “Gain of Toxic Function Hypothesis”, higher concentrations or amylin oligomers/fibrils activating AMYR may cause the activation of Voltage-gated Ca²⁺ ion channels, to open leading to an excitotoxicity state due to chronic intracellular Ca²⁺ in state of disease or pathology, such as AD or Type II Diabetes. Bottom Right: Proposed therapy for this rationale is to block AMYR with antagonists that inhibit potential toxic downstream signaling. Created with BioRender.com.