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

项目总结/摘要 生酮饮食已被提出作为阿尔茨海默病（AD）的治疗，阿尔茨海默病是一种以 tau蛋白的聚集和神经元间扩散。虽然临床前研究和早期阶段 临床试验显示出改善早期AD患者记忆力的良好结果， 生酮饮食减缓AD进展的机制尚不清楚。这样的差距 知识阻碍了具有更高疗效的更精确的基于酮的疗法的开发， 副作用.生酮饮食可能通过多种机制起作用：例如，主要的酮体，β- 羟基丁酸酯（BHB）提供能量来源并且还充当信号分子。解析 这些机制的贡献将有助于确定生酮饮食的哪些成分与 tau蛋白病我们已经发现，补充酮的饮食显著减少了小鼠中的tau扩散。 此外，用BHB处理显著减少了培养的皮质神经元中的tau分泌。整体 本申请的目的是阐明BHB降低 tau扩散和神经变性。核心假设是BHB主要通过以下途径抑制tau扩散： 其信号传导活性，特别是BHB抑制神经元的tau分泌并促进其降解 通过自噬-内溶酶体流。该项目的基本原理是， BHB对tau扩散的临床前治疗功效和机制将可能导致更好的靶向和 用于AD和其他tau蛋白病的更有效的基于酮的药理学疗法。核心假设 将通过追求三个具体目标进行测试：1）确定信号与生物能量的贡献 BHB在小鼠中减少tau扩散和改善神经退行性表型的活性; 2）测定BHB在小鼠中的神经退行性表型; BHB对调节tau蛋白降解、分泌和分泌的自噬-内溶酶体途径（ALP）的影响 3）确定BHB响应于BHB的信号传导对tau相互作用组的影响，以及 生物能量活动。这项拟议中的研究是创新的，因为它解决了未知的问题 生酮饮食对tau蛋白影响的潜在机制，使用药理学， 遗传学、细胞生物学和系统生物学方法在原代和iPSC诱导的神经元培养中， 小鼠模型。拟定研究的结果将弥补酮体如何 影响tau的发病机制并阐明其潜在机制，从而使未来能够开发新的 AD和其他tau蛋白病的治疗策略。

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.