TY - JOUR T1 - Gender-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice JF - bioRxiv DO - 10.1101/803262 SP - 803262 AU - Khaled S. Abd-Elrahman AU - Alison Hamilton AU - Jessica M. de Souza AU - Awatif Albaker AU - Fabiola M. Ribeiro AU - Stephen S. G. Ferguson Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/13/803262.abstract N2 - Gender 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 gender-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 gender-specific AD treatment strategies. ER -