Abstract

The combination of brain glucose hypometabolism and hyperphosphorylated Tau (p-Tau) pathology is the strongest known clinical predictor of imminent cognitive decline, yet how these factors cooperate to drive dementia remains unknown. Here, we show that glucose hypometabolism synergizes with p-Tau to trigger neuronal loss through necroptosis. Under low-glucose conditions, accumulated p-Tau forms a molecular scaffold that directly recruits RIPK1, while concomitant loss of the necroptosis checkpoint A20 removes a critical brake on this death pathway. This dual mechanism thereby precipitates neuronal necroptosis. Restoring A20 expression with acetyl-L-carnitine or preventing the p-Tau-RIPK1 interaction using a RIPK1-derived competitive peptide alleviates neuronal necroptosis and brain atrophy in a Tau transgenic mouse model. Collectively, our findings uncover a previously unrecognized metabolism-driven necroptotic signaling cascade initiated by a p-Tau-RIPK1 hub, providing mechanistic insight into how glucose hypometabolism synergizes with p-Tau to drive neurodegeneration.