Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner

The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although beta-amyloid (A beta) deposition is a pathological hallmark of AD in both sexes. A beta-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to A beta oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective A beta-mGluR5 interaction did not appear to depend on estrogen, but rather AD interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, A beta oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated A beta pathology, and reversed cognitive decline in male APPswe/PS1 Delta E9 mice, but not in their female counterparts. A beta oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to A beta pathology in females, highlighting the complexity of mGluR5 pharmacology and A beta signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.