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September 2nd, 2025
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East China University of Science and Technology
neuroscience
bioRxiv

GSDME unlocks astrocyte-driven neurotoxicity in Alzheimer's Disease

Xie, X.Open in Google Scholar•Ji, C.Open in Google Scholar•Xu, J.Open in Google Scholar•Lu, X.Open in Google Scholar•Guo, G.Open in Google Scholar•Liu, W.Open in Google Scholar•Wu, X.Open in Google Scholar•Chen, Y.Open in Google Scholar•Zhang, Y.Open in Google Scholar•Wang, J.Open in Google Scholaret al.

Astrocytic calcium dysregulation and reactivity precede Abeta; deposition in amyloid-{beta} 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, Abeta-activated microglial signals activate astrocytic GSDME, releasing its N-terminal fragment, which targets MAMs and triggers ER calcium efflux. This induces biphasic CaMKIIalpha; phosphorylation, initially boosting NRF2 defenses, then activating NF-kappaB-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 Abeta; burden, restores NF-kappaB/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.

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