Journal Article

DZNE-2026-00933

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glucose hypometabolism and hyperphosphorylated Tau synergistically drive neuronal necroptosis.

Chen, X. ; Li, S. ; Neubauer, A.DZNE* ; Li, X. ; Mao, W. ; Brendel, M.DZNE* ; Liu, J. ; Zhang, M. ; Yang, C. ; Xu, R. ; Liu, J. ; Shan, B. ; Yuan, J. ; Liu, C. ; Herms, J.DZNE* ; Zou, C.

2026
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.neuron.2026.03.035

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.

Keyword(s): Animals (MeSH) ; tau Proteins: metabolism (MeSH) ; tau Proteins: genetics (MeSH) ; Glucose: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Necroptosis: physiology (MeSH) ; Phosphorylation (MeSH) ; Mice (MeSH) ; Receptor-Interacting Protein Serine-Threonine Kinases: metabolism (MeSH) ; Mice, Transgenic (MeSH) ; Humans (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Signal Transduction (MeSH) ; glucose hypometabolism ; necroptosis ; neurodegeneration ; p-Tau ; tau Proteins ; Glucose ; Receptor-Interacting Protein Serine-Threonine Kinases

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)
2. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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