Abstract

Alzheimer’s disease (AD) is characterized by neurotoxicity mediated by the accumulation of beta amyloid (Aβ) oligomers, causing neuronal loss and progressive cognitive decline. Genetic deletion or chronic pharmacological inhibition of mGluR5 by the negative allosteric modulator CTEP, rescues cognitive function and reduces Aβ aggregation in both APPswe/PS1ΔE9 and 3xTg-AD mouse models of AD. In late onset neurodegenerative diseases, such as AD, defects arise at different stages of the autophagy pathway. Here, we show that mGluR5 cell surface expression is elevated in APPswe/PS1ΔE9 and 3xTg-AD mice. This is accompanied by reduced autophagy (accumulation of p62) as the consequence of increased ZBTB16 expression and reduced ULK1 activity, as we have previously observed in Huntington’s disease (HD). The chronic (12 week) inhibition of mGluR5 with CTEP in APPswe/PS1ΔE9 and 3xTg-AD mice prevents the observed increase in mGluR5 surface expression. In addition, mGluR5 inactivation facilitates the loss of ZBTB16 expression and ULK1 activation as a consequence of ULK-Ser757 dephosphorylation, which promotes the loss of expression of the autophagy marker p62. Moreover, the genetic ablation of mGluR5 in APPswe/PS1ΔE9 mice activated autophagy via similar mechanisms to pharmacological blockade. This study provides further evidence that mGluR5 overactivation contributes to inhibition of autophagy and can result in impaired clearance of neurotoxic aggregates in multiple neurodegenerative diseases. Thus, it provides additional support for the potential of mGluR5 inhibition as a general therapeutic strategy for neurodegenerative diseases such as AD and HD.

Highlights

  • Alzheimer’s disease (AD) is the most prevalent of all the neurodegenerative diseases, with an alarming rise in prevalence as a result of an aging population [1]

  • These results indicated that chronic antagonism of Metabotropic glutamate receptor 5 (mGluR5) with a selective negative allosteric modulator (NAM) could block the increase in cell surface expression of mGluR5 and may contribute to slowing the progression AD pathology and improvement in cognitive function

  • Discussion mGluR5 antagonism using highly-selective mGluR5 NAMs represents a promising approach to slow disease progression and proteotoxic protein aggregation in both AD and Huntington’s disease (HD) [12, 14]

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Summary

Introduction

Alzheimer’s disease (AD) is the most prevalent of all the neurodegenerative diseases, with an alarming rise in prevalence as a result of an aging population [1]. Beta-amyloid (Aβ) protein, a product of amyloid precursor proteins (APP) cleavage that forms soluble oligomers and fibrillar. Metabotropic glutamate receptor 5 (mGluR5) is a member of the G protein-coupled receptor (GPCR) superfamily and when activated by glutamate couples to the heterotrimeric G protein Gαq/11 [7]. MGluR5 functions as an extracellular scaffold for Aβ oligomers. Activation of mGluR5 by Aβ oligomers leads to the release of Ca2+ from intracellular stores and a consequent disruption in synaptic signaling and function [8,9,10]. We have shown that the genetic deletion of mGluR5 in the APPswe/PS1ΔE9 (APPswe) mouse model of AD improved cognitive function and reduced AD pathogenesis [11].

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