Gender-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice

Sex is a key modifier of the prevalence and progression of Alzheimers disease (AD). {beta}- Amyloid (A{beta}) deposition is a pathological hallmark of AD and aberrant activation of metabotropic glutamate receptor 5 (mGluR5) by A{beta} has been linked to AD progression. We find that mGluR5 exhibits distinct sex-dependent pharmacological profiles. Specifically, endogenous mGluR5 from male mouse cortex and hippocampus binds with high-affinity to A{beta} oligomers whereas, female mGluR5 exhibits no affinity to A{beta} oligomers. The binding affinity of mGluR5 to A{beta} oligomer is dependent on its interaction with cellular prion protein (PrPC) as mGluR5 co-immunoprecipitates with PrPC from male, but not female, mouse brain. A{beta} oligomers also bind with high-affinity to human mGluR5 in male, but not female, cortex. The mGluR5/A{beta} oligomer/PrPC ternary complex is essential to elicit mGluR5-dependent pathological signaling and as a consequence mGluR5-regulated GSK3{beta}/ZBTB16 autophagic signaling is dysregulated in male, but not female, primary neuronal cultures. These sex-specific differences in mGluR5 signaling translate into in vivo differences in mGluR5-dependent pathological signaling between male and female AD mice. We show that the chronic inhibition of mGluR5 using a mGluR5-selective negative allosteric modulator reactivates GSK3{beta}/ZBTB16-regulated autophagy, mitigates A{beta} pathology and reverses cognitive decline in male, but not female, APPswe/PS1{Delta}E9 mice. Thus, it is evident that, unlike male brain, mGluR5 does not contribute to A{beta} pathology in female AD mice. This study highlights the complexity of mGluR5 pharmacology and A{beta} oligomer-activated pathological signaling and emphasizes the need for clinical trials redesign and analysis of sex-tailored treatment for AD.