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.

doi:10.64898/2026.01.30.702936

bioRxiv · 10.64898/2026.01.30.702936

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.

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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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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.. 2026-02-02. Ketone body beta-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism. https://doi.org/10.64898/2026.01.30.702936

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