Restoring neuronal glucose metabolism improves bioenergetics and survival in models of MAPT-related frontotemporal dementia

Glucose is the major fuel supporting the high bioenergetic demands of brain cells, and reduced cerebral glucose uptake is a clinical hallmark of neurodegenerative disorders including frontotemporal dementia (FTD). However, how neuronal glucose metabolism is altered in FTD remains incompletely understood. Here, we show that enhancing glycolysis restores cellular and organismal function in neuronal models of MAPT-FTD, a major form of FTD caused by pathogenic MAPT mutations. Across Drosophila and human iPSC-derived neurons carrying FTD-associated MAPT alleles, we observe convergent molecular and metabolomic signatures consistent with altered neuronal glucose metabolism. Functionally, glucose-dependent ATP homeostasis is diminished in MAPT-FTD neurons, indicating compromised coupling between glucose utilization and energy production. Promoting glucose catabolism either through glycolytic enzyme overexpression or inhibition of Sirtuin 6 rescues glucose-dependent bioenergetics in MAPT-FTD neurons. Notably, these interventions improve survival in flies expressing mutant MAPT but not wild-type MAPT, indicative of an allele-specific metabolic vulnerability. Together, our findings identify impaired neuronal glycolytic metabolism and glucose-dependent bioenergetics as conserved features of the MAPT-FTD models and suggest glycolytic enhancement as a strategy to restore neuronal energy homeostasis and improve outcomes in mutant MAPT-driven pathology.