Aβ oligomers induce sex-selective differences in mGluR5 pharmacology and pathophysiological signaling in Alzheimer mice

Abstract

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 mGluR5dependent 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 genderspecific 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. SHORT RUNNING TITLE:Gender-specific Aβ signaling in Alzheimer's disease

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