Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss.

ABSTRACT: Alzheimer's disease (AD) is not only defined by amyloid-β and tau pathology but by early metabolic disruptions and hyperexcitability. How tau independently reshapes the coupling of metabolism-excitability to impact processes like sleep remains unclear. Here, hyperphosphorylated tau preserves whole-body metabolic function while driving cortical hyperexcitability and sleep loss in mouse models of tauopathy. Tau pathology prevented age-related decline in glucose tolerance and maintained diurnal hippocampal interstitial fluid (ISF) glucose and lactate rhythms, which were lost in aging wildtype mice. Stable isotope-resolved metabolomics revealed that tau pathology preferentially shunts glucose toward glutamate synthesis at the expense of GABA, suggesting an excitatory/inhibitory (E/I) imbalance

SUBMITTER: Irmen RE 

PROVIDER: S-EPMC12830363 | biostudies-literature | 2026

REPOSITORIES: biostudies-literature