Colson, T.-L. L. | Search bioRxiv

bioRxiv2026

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.

neuroscience↗

bioRxiv2026

TRIM9 Determines Sex-Specific β-Amyloid/Cellular Prion Protein/mGluR5 Complex Formation and Pathological Signaling in Alzheimer's Disease Mice

Biological sex is a major determinant of Alzheimers disease prevalence, yet the molecular mechanisms underlying sex-specific vulnerability remain largely unknown. Metabotropic glutamate receptor 5 (mGluR5) functions as a co-receptor for {beta}-amyloid (A{beta}42) oligomer/cellular prion protein (PrPC)-mediated pathogenic signaling in males but not females, establishing a sex-dimorphic node in {beta}-amyloid pathophysiology whose regulatory basis is undefined. Using quantitative proteomic analysis, we identify the E3 ubiquitin ligase TRIM9 as a novel mGluR5-interacting protein and a previously unrecognized sex-specific regulator of the A{beta}42/PrPC/mGluR5 complex. TRIM9 selectively associates with mGluR5 in male but not female APP/PS1 mouse brain and is required for mGluR5 to serve as a co-receptor for PrPC-dependent A{beta}42 oligomer binding. Genetic deletion of TRIM9 abolishes A{beta}42/PrPC/mGluR5 complex assembly in male APP/PS1 mice demonstrating that TRIM9 is an essential scaffold for male-specific A{beta}42 signal transduction. Loss of TRIM9 in males further reduces {beta}-amyloid pathology by restoring Akt/GSK3{beta}/ZBTB16-dependent autophagic flux, linking disruption of this complex to a defined downstream proteostatic mechanism. Together, these findings establish TRIM9 as a critical molecular determinant coupling male-specific A{beta}42/PrPC/mGluR5 complex assembly to downstream neurodegenerative signaling and {beta}-amyloid pathology. They reveal an unappreciated layer of sex-dependent complexity in mGluR5 pharmacology and identify disruption of the TRIM9/mGluR5 interaction as a potential male-specific therapeutic strategy for Alzheimers disease. Significance StatementThe molecular basis of sex differences in Alzheimers disease vulnerability remains unresolved. We show that mGluR5 functions as a male-specific co-receptor for pathogenic A{beta}42/PrPC signaling and identify the E3 ubiquitin ligase TRIM9 as the factor governing this dimorphism. TRIM9 selectively assembles the A{beta}42/PrPC/mGluR5 complex in male brain, and its genetic deletion disrupts complex formation while restoring Akt/GSK3{beta}-dependent autophagic clearance of amyloid. These findings define a sex-specific signaling axis underlying {beta}-amyloid pathogenesis and establish TRIM9 as a candidate target for sex-informed Alzheimers therapeutics.

neuroscience↗