Glucose hypometabolism and hyperphosphorylated Tau synergistically drive neuronal necroptosis
Chen, X.; Li, S.; Neubauer, A.; Li, X.; Mao, W.; Brendel, M.; Liu, J.; Zhang, M.; Yang, C.; Xu, R.; Liu, J.; Shan, B.; Yuan, J.; Liu, C.; Herms, J.; Zou, C.
Show 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 the necroptotic kinase RIPK1, while concomitant loss of the necroptosis checkpoint protein A20 removes a critical brake on this death pathway. This dual mechanism thereby precipitates neuronal necroptosis independent of classical TNF/TNFR1 signaling paradigm. Restoring A20 expression with acetyl-L-carnitine as a dietary supplement 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 mechanical insight into how glucose hypometabolism synergizes with p-Tau to drive neurodegeneration.
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