Ketone body beta-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism
Rossitto, L.-A. M.; Foo, J.; Di Silvestri, J. M.; Lehmann, L.; Brunelli, M.; Nie, Y.; Munoz-Mayorga, D.; Xiao, Q.; Dai-Liu, A. Y.; Jati, S.; Rossi, M.; Daneman, R.; Kelly, J. W.; Newman, J. C.; Myers, S. A.; Chen, X.
Show abstract
Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimers disease (AD) and related tauopathies. {beta}-hydroxybutyrate ({beta}HB), 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 {beta}HB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across in vitro, ex vivo, and in vivo models, we find that {beta}HB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of {beta}HBs oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position {beta}HB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.
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