β-Arrestin2 Drives Sex-Specific Akt/GSK3β Signaling, Aβ Pathology, and Cognitive Decline in Alzheimer’s Disease Mice

Sex is a major determinant of Alzheimer’s disease risk and progression, yet the molecular mechanisms underlying this dimorphism remain poorly defined, limiting the development of sex-informed therapeutics. β-Arrestin2 is a pervasive, multifunctional regulator common to a host of G protein-coupled receptors (GPCRs) in the brain, but whether it has a sex-dependent role in Alzheimer’s disease is unknown. Here, we demonstrate that β-arrestin2 deficiency produces sexually dimorphic effects on Aβ pathology, neuroinflammation, cognition and autophagic flux in APPswe/PS1ΔE9 (APP/PS1) mice. In males, Arrb2 deletion reduced Aβ oligomer burden, enhanced autophagy, suppressed astrocytic and microglial reactivity, and broadly rescued cognition encompassing spatial working memory, spatial learning, cognitive flexibility, and recognition memory. In females, Aβ pathology and astrogliosis was unchanged and microgliosis was enhanced, with cognitive improvement limited to recognition memory. The male-specific reduction in pathology was accompanied by decreased S473-Akt and S9-GSK3β phosphorylation and enhanced GSK3β/ZBTB16-mediated autophagy, identifying β-arrestin2 as a molecular switch driving sex-restricted Aβ pathology, glial activation, and cognitive decline in male APP/PS1 mice. These findings identify β- arrestin2 as a sex-dependent node linking Aβ pathology to cognitive outcomes in males but not females, underscoring the necessity of sex-stratified consideration in the design of GPCR-targeted Alzheimer’s disease therapeutics.