Tau pathology reprograms glucose metabolism to support glutamatergic activity and excitatory imbalance

Alzheimer's disease (AD) is not only characterized by amyloid-beta (Aβ) and tau pathology, but also by early and progressive disruptions in metabolism. Neuronal excitability is tightly coupled with metabolic demand, and aberrant excitatory activity - observed in AD patients and models - can drive changes in metabolism. While Aβ-related metabolic impairments are well-described, less is known about how tau pathology independently contributes to altered metabolic states and excitatory tone. Therefore, we explored how tau pathology impacted whole body and CNS metabolism in mouse models of tauopathy, including the P301S PS19 and Tau4RTg2652 mice. In both models, hyperphosphorylated tau prevents the age-related decline in whole-body metabolism by preserving glucose tolerance and mitigating shifts in fuel utilization (respiratory exchange ratio; RER), suggesting the mice are "glucose needy". Tau pathology also preserves diurnal rhythms in hippocampal interstitial fluid (ISF) glucose and lactate, likely due to increased neuronal activity during the active (dark) phase. Stable isotope-resolved metabolomics following ¹³ C-glucose administration revealed that glucose is preferentially shunted toward glutamate synthesis-at the expense of GABA-highlighting a shift in excitatory/inhibitory balance. Interestingly, these changes were not explained by a primary deficit in synaptic mitochondria but by alterations in glycolytic flux. Adaptations were time of day dependent, where ISF glutamate rises after a glucose injection in the dark period but not the light period. This suggests increased glutamatergic activity may drive metabolic demand during the dark period when mice are more active. Together, these studies fundamentally highlight the important coupling between metabolism and excitability, which is disrupted by hyperphosphorylated tau, tau aggregation, and neurodegeneration. Understanding how tau pathology and metabolism interrelate provides a novel lens for the development of therapeutic targets in late stage AD.