Glycolysis and Alzheimer’s Disease

糖酵解和阿尔茨海默病

• 批准号: 10516234
• 负责人: Qiang Zhang
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516234
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Animal Model; Automobile Driving; Autopsy; Binding; Biochemistry; Biogenesis; Biological Assay; Biology; Blood; Brain; Caloric Restriction; Clinical Trials; Data; Databases; Diabetes Mellitus; Disease; Enzyme-Linked Immunosorbent Assay; Exercise; Future; Generations; Glycolysis; Goals; Healthcare; Human; Image; Immunohistochemistry; Impaired cognition; Impairment; Intervention; Magnetic Resonance Spectroscopy; Measures; Medicare; Medicare claim; Metabolic Diseases; Metabolism; Mitochondria; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Obesity; Oral; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Phosphoglycerate Kinase; Physiology; Pre-Clinical Model; Process; Risk; Risk Factors; Rodent; Rodent Model; Short-Term Memory; Techniques; Testing; Transgenic Organisms; Western Blotting; Work; amyloid pathology; antagonist; base; brain dysfunction; cognitive function; effective therapy; epidemiology study; fluorodeoxyglucose positron emission tomography; glucose metabolism; improved; in vivo; in vivo magnetic resonance spectroscopy; metabolomics; mouse model; multidisciplinary; neuroimaging; neuron loss; novel; object recognition; preclinical study; prevent; protein aggregation; tamsulosin; tau Proteins; tau aggregation; terazosine

Project Summary Alzheimer's disease (AD) is a devastating disease with no disease-modifying therapies. A key contributing factor to AD is impaired glucose metabolism. However, it is unknown how glucose metabolism contributes to neurodegeneration in AD. Our recent work demonstrated that we could enhance glycolysis via an existing drug, terazosin (TZ). This drug is an alpha-1 antagonist, but it also binds to and enhances activity of phosphoglycerate kinase-1 (PGK1), the first ATP-generating step of glycolysis. Excitingly, our preliminary data from the Truven database of Medicare claims suggest that patients taking TZ are protected from developing AD relative to those taking tamsulosin, another alpha-1 antagonist that does not bind PGK1. Additionally, our review of the Alzheimer's Disease Neuroimaging initiative (ADNI) indicates that patients taking TZ have slower progression on FDG-PET and on cognitive impairment, compared to those taking tamsulosin. In this proposal, our goal is to test TZ target engagement and efficacy in animal models of AD. To our knowledge, no drug for AD directly engages PGK1 or metabolism and mitigates protein aggregation; thus, this mechanism is entirely novel for AD. Our overall hypothesis is that TZ is protective in rodent models of AD. In Aim 1, we will quantify TZ target engagement in rodent AD models. We will administer TZ orally for six-months to transgenic tau (P301S) and amyloid (5XFAD) mice relevant for human AD, along with littermate and vehicle controls. We will evaluate blood and brain metabolomics and [ATP], as well as in vivo magnetic resonance spectroscopy (MRS). In Aim 2, we will evaluate whether improving glycolysis mitigate neurodegeneration in rodent AD models. We will use the same mice as in Aim 1 and evaluate cognitive function via novel-object recognition, spatial working memory, and interval timing assays. We will also perform immunohistochemistry, ELISA, and western blot to assess tau/amyloid pathology. These studies will elucidate the basic principles of how TZ enhances brain energetics, and affects neurodegeneration. These fundamental mechanisms could be highly relevant for inspiring novel disease-modifying therapies in AD and related dementias.

项目摘要 阿尔茨海默病（AD）是一种毁灭性的疾病，没有疾病修饰疗法。一个关键 导致AD的因素是糖代谢受损。然而，目前尚不清楚葡萄糖 代谢导致AD中的神经变性。我们最近的研究表明， 通过现有的药物特拉唑嗪（TZ）增强糖酵解。这种药物是α-1拮抗剂，但它也 结合并增强磷酸甘油酸激酶-1（PGK 1）的活性，这是磷酸甘油酸激酶-1（PGK 1）的第一个ATP生成步骤， 糖酵解令人兴奋的是，我们从Truven医疗保险索赔数据库中获得的初步数据表明， 与服用坦索罗辛的患者相比，服用TZ的患者不会发展为AD， 不结合PGK 1的α-1拮抗剂。此外，我们对阿尔茨海默病的回顾 神经影像学倡议（ADNI）表明，服用TZ的患者在FDG-PET上进展较慢 和认知障碍的影响。在这个提案中，我们的目标是测试 AD动物模型中的TZ靶标接合和功效。据我们所知，没有直接治疗AD的药物， 参与PGK 1或代谢并减轻蛋白质聚集;因此，这种机制完全是 小说AD我们的总体假设是TZ在AD的啮齿动物模型中具有保护作用。在目标1中，我们 定量啮齿动物AD模型中的TZ靶标接合。我们将口服TZ六个月， 与人AD相关的转基因tau（P301 S）和淀粉样蛋白（5XFAD）小鼠，沿着同窝出生， 车辆控制。我们将评估血液和大脑代谢组学和[ATP]，以及体内磁共振成像。 共振波谱（MRS）。在目标2中，我们将评估改善糖酵解是否能减轻 啮齿动物AD模型中的神经变性。我们将使用与目标1中相同的小鼠并评估 认知功能，通过新的物体识别，空间工作记忆，和时间间隔测定。我们 还将进行免疫组织化学、ELISA和蛋白质印迹以评估tau/淀粉样蛋白病理学。 这些研究将阐明TZ如何增强大脑能量学的基本原理， 神经变性这些基本机制可能与激发小说灵感高度相关。 AD和相关痴呆的疾病改善疗法。