Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer\u2019s Disease Mouse Models

Aarti Patel,Jing Yang,David Mactavish,Rachel A Davey,David Westaway,Wen Fu,Ryoichi Kimura,Jack H Jhamandas,Jeffrey D Zajac,Rania Soudy

doi:10.1007/s12035-021-02490-y

Abstract

Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

Highlights

A defining pathological feature of Alzheimer’s disease (AD) is the presence of soluble oligomers of amyloid beta (Aβ) that aggregate into extracellular fibrillary deposits known as amyloid β-plaques [1]
We have shown that human amylin, a 37-amino acid peptide identified in pancreas of diabetics, causes neurotoxicity in a manner very similar to amyloid β peptide (Aβ), and that the effects of the human amylin and Aβ on neurons appear to be expressed via the same receptor, the amylin receptor, a class B G protein-coupled receptor [4]
The amylin receptor, a class B G protein-coupled receptor (GPCR), is viewed as a plausible therapeutic target for AD based upon observations that modulation of this receptor by either synthetic amylin analogs or amylin antagonists confers improvement in spatial memory and learning [6,7,8, 16, 17]

Summary

Introduction

A defining pathological feature of Alzheimer’s disease (AD) is the presence of soluble oligomers of amyloid beta (Aβ) that aggregate into extracellular fibrillary deposits known as amyloid β-plaques [1]. Synaptic disruption, neuroinflammation, and vasculopathy are key perturbations of AD pathology and each is linked to the presence of Aβ in the brain [1, 3]. Aβ protein has been shown to interact with a number of G protein-coupled receptors (GPCRs) to modulate major cognitive and pathological features of AD and has become attractive therapeutic targets for the development of disease-modifying treatments for AD. We have shown that human amylin, a 37-amino acid peptide identified in pancreas of diabetics, causes neurotoxicity in a manner very similar to Aβ, and that the effects of the human amylin and Aβ on neurons appear to be expressed via the same receptor, the amylin receptor, a class B G protein-coupled receptor [4].

Methods

Results

Conclusion