GSDME unlocks astrocyte-driven neurotoxicity in Alzheimer’s Disease

Astrocytic calcium dysregulation and reactivity precede Aβ deposition in amyloid-β deposition in Alzheimer’s disease (AD) but the neurotoxic mechanisms remain unclear. We show that GSDME acts as a switch, linking MAM-mediated calcium release to astrocyte-driven neurotoxicity. Specifically, Aβ-activated microglial signals activate astrocytic GSDME, releasing its N-terminal fragment, which targets MAMs and triggers ER calcium efflux. This induces biphasic CaMKIIα phosphorylation, initially boosting NRF2 defenses, then activating NF-κB-driven inflammation, shifting astrocytes from protective to toxic states. GSDME activation also drives astrocyte-derived exosomes (ADEs) to carry neurotoxic tau, proinflammatory miRNAs, and toxic lipids, propagating toxicity. GSDME deletion in AD mice reduces Aβ burden, restores NF-κB/NRF2 balance, reprograms astrocytes and ADEs to protective states, and rescues cognition. Multi-omics profiling of serum ADEs from AD patients reveals a disease-specific signature with central neurotoxicity and peripheral immune regulation. These findings position GSDME as a promising dual diagnostic and therapeutic target for early AD invention.