Blocking estrogen receptors restores surface mGluR5 but not downstream signaling in female APP/PS1 Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) regulation of autophagy and accelerates disease progression in male AD mouse models. Yet, mGluR5 contribution to Aβ pathology is not observed in female AD mice, suggesting a distinct sex-selective profile. Given that estrogen receptors (ERs) form functional complexes with mGluR5 selectively in females, we assessed the role of ER activity in mGluR5 expression and downstream signaling in APPswe/PS1ΔE9 (APP/PS1) mice. We report here that mGluR5 cell surface expression is elevated in male but reduced in female APP/PS1 cortex relative to sex-matched wildtype controls, with total receptor expression remaining unchanged in both sexes. Treatment with the ER blocker, ICI 182,780, restored mGluR5 cell surface expression in female APP/PS1 mice but failed to rescue GSK3β and ULK1-regulated autophagy signaling. These findings indicate that male and female mGluR5 are embedded within intrinsically distinct signaling interactomes that are independent of ER regulation.