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

酮体β-羟基丁酸抵消 tau 发病机制的机制

• 批准号: 10449007
• 负责人: Xu Chen
• 金额: $ 54.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449007
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Animals; Autophagocytosis; Bioenergetics; Biological Process; Brain; CRISPR interference; Carbohydrates; Cell Culture System; Cell Nucleus; Cells; Cellular biology; Chronic; Clinical Trials; Cognitive; Coupled; Data; Development; Diet; Disease; Disease Progression; Energy-Generating Resources; Enzymes; Epilepsy; Event; Fatty acid glycerol esters; Future; Genetic; Glucose; Goals; Human; In Vitro; Individual; Intervention; Ketone Bodies; Ketones; Knock-out; Knowledge; Label; Link; Mass Spectrum Analysis; Mediating; Memory; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Genetics; Motor Neurons; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Phase I Clinical Trials; Prevention; Production; Proteins; Reducing diet; Regulation; Research; Role; Signal Transduction; Signaling Molecule; Small Nuclear RNA; Systems Biology; Tauopathies; Testing; Therapeutic; Tissue Banks; Transgenic Mice; Treatment Efficacy; Tweens; Vesicle; aged; base; behavioral phenotyping; beta-Hydroxybutyrate; brain cell; cell type; cognitive function; effective intervention; enantiomer; fly; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; juvenile animal; ketogenic diet; metabolic phenotype; mouse model; neurodegenerative phenotype; novel; oxidation; pre-clinical; preclinical study; prevent; protective effect; protein protein interaction; proteostasis; recruit; response; side effect; targeted treatment; tau Proteins; tool; trafficking; transcriptome; transcriptome sequencing; treatment strategy

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.

项目摘要/摘要 生酮饮食已被提出用于治疗阿尔茨海默病(AD)，这种疾病的特点是 Tau蛋白的聚集和神经元间扩散。尽管临床前研究和早期阶段 临床试验显示，在改善早期阿尔茨海默病患者的记忆力方面，有希望的结果 生酮饮食延缓AD进展的机制(S)尚不清楚。这样的差距 知识阻碍了更精确的基于酮的疗法的发展，这些疗法具有更高的疗效和更低的 副作用。生酮饮食可能通过多种机制发挥作用：例如，主要的酮体β- 羟基丁酸酯(BHB)，提供能量来源，也是一种信号分子。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 紧张症。我们发现，补充酮的饮食显著减少了tau在小鼠中的传播。 此外，BHB处理显著减少培养的皮质神经元的tau分泌。整体而言 本应用的目的是阐明BHb降低的细胞和分子机制(S 牛磺酸扩散和神经变性。中心假设是BHB主要通过以下途径抑制tau的传播 它的信号活性，特别是bhb抑制神经元tau的分泌，促进tau的降解。 通过自噬-内溶酶体通量。这个项目的基本原理是确定 补肾活血方治疗tau扩散的临床前疗效及作用机制(S) 更有效的以酮为基础的药物治疗阿尔茨海默病和其他牛皮病。中心假说 将通过追求三个具体目标进行测试：1)确定信号相对于生物能量的贡献 BHB抑制tau蛋白扩散和改善小鼠神经退行性变表型的活性；2)测定 牛血清白蛋白对自噬-内溶酶体途径调节tau降解、分泌和释放的影响 传播，以及3)确定BHB对tau相互作用组的影响，以响应BHB的信号和 分别具有生物能量活性。这项拟议的研究具有创新性，因为它解决了未知的问题 生酮饮食对tau影响的潜在机制，结合药理学， 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的应用 老鼠模型。拟议中的研究结果将弥合关于酮体如何 影响tau的发病机制，阐明其潜在的机制，从而为今后的研究开发奠定基础 阿尔茨海默病和其他紧张性疾病的治疗策略。