Ketone body β-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism

Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimer's disease (AD) and related tauopathies. β-hydroxybutyrate (βHB), the primary ketone body produced during ketosis, reproduces key features of these metabolic interventions, but the molecular mechanism underlying its neuroprotective properties is not fully understood. Here, we demonstrate that a βHB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across <i>in vitro</i>, <i>ex vivo</i>, and <i>in vivo</i> models, we find that βHB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of βHB's oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position βHB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.