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

基本信息

批准号：
10612459
负责人：
Xu Chen
金额：
$ 58.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10612459
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Animals Autophagocytosis Bioenergetics Biological Process Brain CRISPR interference Carbohydrates Cell Culture System Cells Cellular biology Chronic Clinical Trials Coupled Data Development Diet Disease Disease Progression Energy-Generating Resources Enzymes Epilepsy Event Fatty acid glycerol esters Frontotemporal Dementia Future Genetic Glucose Goals Human Impaired cognition In Vitro Individual Interneurons Intervention Ketone Bodies Ketones Knock-out Knowledge Label Link Mass Spectrum Analysis Mediating Memory Metabolic Pathway Metabolism Modeling Molecular Motor Neurons Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathway interactions Pharmacology Phase I Clinical Trials Prevention Production Proteins Publications Reducing diet Regulation Reporting Repression Research Role Signal Transduction Signaling Molecule Systems Biology Tauopathies Testing Therapeutic Tissue Banks Transgenic Mice Treatment Efficacy Vesicle aged 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 neuropathology novel oxidation pharmacologic pre-clinical preclinical study prevent protective effect protein protein interaction proteostasis recruit response side effect single nucleus RNA-sequencing targeted treatment tau Proteins tau interaction tool trafficking transcriptome treatment strategy

项目摘要

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.

项目概要/摘要生酮饮食已被提议作为阿尔茨海默病（AD）的治疗方法，这种疾病的特征是 tau 蛋白的聚集和神经元间扩散虽然处于临床前研究和早期阶段。临床试验显示，早期 AD 患者的记忆力得到改善，效果良好。生酮饮食减缓 AD 进展的机制尚不清楚。知识阻碍了更精确、更高效的基于酮的疗法的开发，并减少了生酮饮食可能通过多种机制发挥作用：例如，主要酮体，β-。羟基丁酸（BHB），提供能量来源，也充当解析信号分子。这些机制的贡献将有助于确定生酮饮食的哪些组成部分与我们发现补充酮的饮食可显着减少小鼠体内的 tau 扩散。此外，BHB 治疗显着减少了培养的皮质神经元中 tau 的分泌。本申请的目的是阐明 BHB 减少的细胞和分子机制 tau 扩散和神经变性的中心假设是 BHB 主要通过抑制 tau 扩散发挥作用。其信号传导活性，特别是 BHB 抑制神经元分泌 tau 蛋白并促进其降解通过自噬-内溶酶体通量。该项目的基本原理是确定 BHB 对 tau 扩散的临床前治疗功效和机制可能会导致更好的靶向和治疗针对 AD 和其他 tau 病更有效的基于酮的药物疗法。将通过追求三个具体目标进行测试：1）确定信号传导与生物能量的贡献 BHB 在减少小鼠 tau 扩散和改善神经退行性表型方面的活性 2) 确定 BHB 对自噬-内溶酶体途径 (ALP) 调节 tau 降解、分泌和传播，以及 3) 确定 BHB 对 tau 相互作用组的影响，以响应 BHB 的信号传导和所提出的研究是创新的，因为它解决了未知的问题。结合药理学，研究生酮饮食对 tau 蛋白影响的机制，原代和 iPSC 诱导的神经元培养中的遗传学、细胞生物学和系统生物学方法、果蝇和小鼠模型的研究结果将弥补酮体如何产生的知识空白。影响 tau 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。