Ketone body ß-hydroxybutyrate restores Tau proteostasis via metabolism-independent mechanism

Alzheimer's disease (AD) and related tauopathies are marked by brain accumulation of pathological Tau aggregates and associated metabolic dysfunction. Metabolic interventions including ketogenic diets, caloric restriction, and exercise have shown promise in ameliorating cognitive impairments in AD, but variable efficacy and issues of compliance and side effects mar their translational potential. A shared molecular feature between these interventions is the induction of ketosis, a metabolic state marked by elevated circulating levels of ß-hydroxybutyrate (ßHB). Previous studies show ßHB administration directly or in the form of a precursor can reproduce and even improve upon the benefits of metabolic interventions, but the molecular mechanism underlying the neuroprotective properties of ßHB in AD remains to be elucidated. In the current study, we find that a ßHB precursor diet is sufficient to ameliorate Tau pathophysiology in the PS19 mouse model at both the pathological and single-cell levels. This GEO record is for the hippocampal single nucleus RNA sequencing data generated for our diet paradigm. Overall design: Male mice, either PS19 hTau+ or WT littermate controls, were switched from standard vivarium chow to either a ketone ester diet (KE) or a macro-controlled diet (CTL) at six months of age until about 9.5 months of age. At this time, mice were perfused with cold PBS, and hippocampi were dissected on ice, flash frozen, and stored at -80C until nuclei extraction. Three mice per group were included in this sequencing experiment for a total of 12 samples.