Short amylin receptor antagonist peptides improve memory deficits in Alzheimer\u2019s disease mouse model

Rania Soudy,Jack Jhamandas,Ryoichi Kimura,Kamaljit Kaur,Aarti Patel,David Westaway,Jing Yang,Wen Fu

doi:10.1038/s41598-019-47255-9

Abstract

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12–14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY within the peptides is an essential sequence for preservation of the beneficial effects of the fragments that we report here and constitutes a new pharmacological target. These findings suggest that the amylin receptor antagonism may represent a novel therapy for AD.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia that affects over 44 million individuals worldwide, and its prevalence of this condition continues to rise[1]
A peptide library membrane was incubated with green fluorescent protein (GFP) labeled amylin receptor subtype 3 (AMY3)-expressing HEK293 cells (HEK-AMY3) to identify the highly binding sequences (Supplemental Fig. S1B)
To evaluate amylin receptor specificity of binding, the library was further screened against transfected calcitonin receptor (CTR), and Wild-type HEK293 cells (HEK-WT). (Supplemental Fig. S1C)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia that affects over 44 million individuals worldwide, and its prevalence of this condition continues to rise[1]. A recent study demonstrated that intracerebroventricular (icv) infusions of AC253 or intraperitoneal administration of the brain penetrant cyclized AC253 (cAC253), improved age-dependent deficits in spatial memory and learning in transgenic AD mice without gross adverse effects[21] These antagonists improved synaptic markers along with suppression of microglial activation and neuroinflammation[21]. The presence of amylin peptides in the circulation was postulated to serve as a “peripheral sink” for the egress of amyloid across the blood brain barrier and deemed to involve amylin receptors located on endothelial cells[23] These studies identify the amylin receptor as a viable and potentially promising target for the development of AD therapeutics. In experimental in vitro and in vivo transgenic AD models, these peptide fragments show a significant improvement in memory and learning, and an attenuation of some characteristic features of AD pathology

Methods

Results

Conclusion