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

Sex is a major determinant of Alzheimers disease risk and progression, yet the molecular mechanisms underlying this dimorphism remain poorly defined, limiting the development of sex-informed therapeutics. {beta}-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 Alzheimers disease is unknown. Here, we demonstrate that {beta}-arrestin2 deficiency produces sexually dimorphic effects on A{beta} pathology, neuroinflammation, cognition and autophagic flux in APPswe/PS1{Delta}E9 (APP/PS1) mice. In males, Arrb2 deletion reduced A{beta} 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, A{beta} 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-GSK3{beta} phosphorylation and enhanced GSK3{beta}/ZBTB16-mediated autophagy, identifying {beta}-arrestin2 as a molecular switch driving sex-restricted A{beta} pathology, glial activation, and cognitive decline in male APP/PS1 mice. These findings identify {beta}- arrestin2 as a sex-dependent node linking A{beta} pathology to cognitive outcomes in males but not females, underscoring the necessity of sex-stratified consideration in the design of GPCR-targeted Alzheimers disease therapeutics.