RT Journal Article
SR Electronic
T1 Sex-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 803262
DO 10.1101/803262
A1 Khaled S. Abd-Elrahman
A1 Alison Hamilton
A1 Jessica M. de Souza
A1 Awatif Albaker
A1 Fabiola M. Ribeiro
A1 Stephen S. G. Ferguson
YR 2019
UL http://biorxiv.org/content/early/2019/10/15/803262.abstract
AB Sex is an important modifier of Alzheimer’s disease (AD) prevalence and progression. Aβ oligomers engage metabotropic glutamate receptor 5 (mGluR5) to mediate pathological signaling in AD. We find here, that mGluR5 signaling is intrinsically different in male versus female mouse neurons, as mGluR5 agonist and Aβ oligomer treatments inactivate a GSK3β/ZBTB16/ATG14-regulated autophagy pathway via Ser9 phosphorylation of GSK3β in an mGluR5-dependent mechanism in male, but not female, primary neuronal cultures. These observed sex-specific differences in mGluR5 signaling translate into in vivo differences in mGluR5-dependent pathological signaling in male and female AD mice. We demonstrate that treatment of male, but not female, APPswe/PS1ΔE9 mice with the mGluR5-selective negative allosteric modulator (NAM), CTEP, improved cognition, reduced Aβ oligomer-mediated pathology, attenuated inflammatory responses and enhanced autophagy in only male APPswe/PS1ΔE9 mice. These differences in male versus female APPswe/PS1ΔE9 responses to CTEP correlate with sex-specific differences in cell surface mGluR5 trafficking. This study demonstrates clear sex-specific differences in mGluR5 cellular signaling and trafficking in a mouse model of AD and strongly indicates a need to redesign and reanalyze sex-specific AD treatment strategies.