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：
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
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/10449007
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 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

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 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

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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.

项目摘要/摘要已提出了生酮饮食作为治疗阿尔茨海默氏病（AD）的治疗方法，该疾病以这种疾病为标志蛋白质tau的聚集和神经元扩散。尽管如此，临床前研究和早期阶段临床试验已显示出对早期AD患者的记忆的有望结果，生酮饮食减慢广告进展的机制尚不清楚。这样的差距知识可以防止开发更精确的基于酮的疗法，并降低副作用。生酮饮食可能通过多种机制作用：例如，主酮体，β- 羟基丁酸（BHB）提供了一种能源，还充当信号分子。解析这些机制的贡献将有助于定义哪些酮饮食的组成部分与 tauopathies。我们发现，补充酮的饮食可显着降低小鼠的tau传播。另外，用BHB治疗显着降低了培养的皮质神经元中的Tau分泌。总体本应用中的目标是阐明BHB降低的细胞和分子机制 tau扩散和神经退行性。中心假设是BHB作用抑制Tau通过其信号活性，特别是BHB反映了神经元的Tau分泌，并促进其降解通过自噬 - 内溶性通量。该项目的理由是确定 BHB对tau蔓延的临床前疗法有效性和机制可能会导致更好的目标，并且针对AD和其他tauopathies的更有效的基于酮的药物疗法。中心假设将通过追求三个具体目标来测试：1）确定信号经文的贡献 BHB在减少tau扩散和改善小鼠神经退行性表型方面的活性； 2）确定 BHB对自噬 - 内溶性途径（ALP）对TAU降解，分泌和分泌调节的影响 3）确定BHB对BHB的信号传导和生物能活性分别。拟议的研究具有创新性，因为它解决了未知的生酮饮食对Tau作用的基础机制，结合了药理学的组合遗传学，细胞生物学和系统生物学方法在原发性和IPSC诱导的神经元培养，苍蝇和鼠标模型。拟议的研究的结果将弥合酮体的知识差距影响tau发病机理并阐明潜在的机制，从而实现新的发展 AD和其他tauopath的治疗策略。