Mechanisms by which the ketone body β-hydroxybutyrate counteracts tau pathogenesis

PROJECT SUMMARY/ABSTRACT The ketogenic diet has been proposed as a treatment for Alzheimer’s disease (AD), a disease marked by the aggregation and inter-neuronal spreading of the protein tau. Although preclinical studies and early stage clinical trials have shown promising results on improved memory in individuals with early AD, the mechanism(s) by which the ketogenic diet slows AD progression is not well understood. Such gap of knowledge prevents the development of more precise ketone-based therapies with higher efficacy and reduce side effects. The ketogenic diet might act through multiple mechanisms: for example, the main ketone body, β- hydroxybutyrate (BHB), provides an energy source and also acts as a signaling molecule. Parsing the contribution of these mechanisms will help define which components of ketogenic diet are most relevant to tauopathies. We have found that a ketone-supplemented diet significantly reduced tau spread in mice. Additionally, treatment with BHB markedly reduced tau secretion in cultured cortical neurons. The overall objectives in this application are to elucidate the cellular and molecular mechanism(s) by which BHB reduces tau spread and neurodegeneration. The central hypothesis is that BHB acts to inhibit tau spread primarily via its signaling activity, and specifically, BHB represses tau secretion from neurons and promotes its degradation through the autophagic-endolysosomal flux. The rationale for this project is that a determination of the preclinical therapeutic efficacy and mechanism(s) of BHB on tau spread will likely lead to better targeted and more effective ketone-based pharmacological therapies for AD and other tauopathies. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the contribution of signaling verses bioenergetic activity of BHB in reducing tau spread and improving neurodegenerative phenotypes in mice; 2) Determine the effects of BHB on the autophagy-endolysosomal pathway (ALP) in regulation of tau degradation, secretion and propagation, and 3) Determine the impact of BHB on the tau interactome in response to BHB’s signaling and bioenergetic activity, respectively. The proposed research is innovative because it tackles the unknown mechanisms underlying the effects of the ketogenic diet on tau, using a combination of pharmacology, genetics, cell biology and system biology approaches in primary and iPSC-induced neuronal culture, fly and mouse models. Results from the proposed studies will bridge the knowledge gap of how the ketone body affects tau pathogenesis and elucidate the underlying mechanisms, thus enable future development of novel treatment strategies for AD and other tauopathies.