Mitochondria targeting for Alzheimer's Disease

线粒体靶向治疗阿尔茨海默病

• 批准号: 10363259
• 负责人: Marcus Laird Forrest
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363259
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease therapy; Animals; Award; Biochemical; Bioenergetics; Biological; Brain; Clinical; Coupling; Defect; Dementia; Development; Dose; Energy Metabolism; Glucose; Glycolysis; Human; Impaired cognition; Ketone Bodies; Laws; Magnetic Resonance Spectroscopy; Medicine; Metabolic; Mitochondria; NADH; Oxaloacetates; Oxidation-Reduction; Parents; Parietal; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase Ib Clinical Trial; Play; Positron-Emission Tomography; Prodrugs; Propylene Glycols; Pyruvate; Reduced Glutathione; Respiration; Role; Scanning; Senile Plaques; Testing; Transgenic Mice; Wild Type Mouse; age related; aged; amyloid pathology; beta-Hydroxybutyrate; brain metabolism; cerebral amyloidosis; fluorodeoxyglucose; glucose metabolism; improved; ketogentic; mitochondrial dysfunction; novel strategies; novel therapeutics

PROJECT SUMMARY OF PARENT AWARD Decreased energy metabolism is an invariant feature of the brains of Alzheimer's disease (AD) patients, yet the specific use of pharmacologic strategies to manipulate energy metabolism in the brain remains relatively untested. We have developed a new approach to treating AD that utilizes fundamental biochemical principles such as the law of mass action, and additionally exploits redox ratios (in particular NAD+/NADH coupling) that gate some bioenergetic fluxes. Our overarching hypothesis is that enhancing brain respiration flux, glycolysis flux, or both will benefit AD patients. We have created new drugs that induce a near-ketogenic state, which we propose will enhance brain metabolism and reduce amyloid pathology. The purpose of this exploratory R21 proposal is test our hypothesis that our new “bioenergetic” drug approach will increase brain energy utilization and reduce amyloid plaque formation in both aged wild-type and transgenic mice. We recently completed a Phase 1B clinical trial of the bioenergetic compound oxaloacetate (OAA) in AD patients with mild dementia (NCT02593318), which showed increased default mode network brain glucose utilization by 18FDG-PET and increased parietal and frontoparietal reduced glutathione on magnetic resonance spectroscopy (MRS) scans. However, enhancement was only seen at the highest doses of 2g/day. We have developed new prodrugs that combine OAA with additional bioenergetic molecules that we propose will enhance ketone bodies and pyruvate levels in the brain, synergistically increasing brain metabolism. Aim 1 will test our hypothesis that prodrugs of OAA and β-hydroxybutyrate (BHB) or propylene glycol (PG) can increase available ketone bodies and pyruvate levels, respectively, and affect brain metabolism. Aim 2 will further test this hypothesis in transgenic mice that have rapid accumulation of amyloid plaques (5xFAD). We will further verify activity in aged wild-type mice, which more accurately recapitulate the whole body (and thus brain) declines in mitochondria function and imbalances in ketone bodies and glucose metabolism. In summary, bioenergetic medicine, i.e. the correction of age-induced mitochondria dysfunction, is a fundamentally different approach to AD therapy from current clinical approaches. The biological studies we propose here could show that there is a firm rationale to develop new clinical drugs that take advantage of multiple bioenergetic mechanisms to reduce brain amyloidosis and age-related brain metabolic decline – spurring development of bioenergetic pharmaceutical approaches.

帕萨特奖项目总结 能量代谢降低是阿尔茨海默病（AD）患者大脑的不变特征，但 具体使用药理学策略来操纵大脑中的能量代谢仍然相对 未经测试我们已经开发出一种新的方法来治疗AD，利用基本的生物化学原理 例如质量作用定律，并且另外利用氧化还原比率（特别是NAD+/NADH偶联）， 控制一些生物能量流我们的首要假设是，增强大脑呼吸流量，糖酵解， 通量，或两者都将有益于AD患者。我们已经创造了新的药物，诱导近生酮状态，我们 建议将增强大脑代谢和减少淀粉样病变。 这个探索性的R21提案的目的是测试我们的假设，我们的新的“生物能量”药物 这种方法将增加脑能量利用，减少老年野生型和 转基因小鼠。我们最近完成了生物能量化合物草酰乙酸的1B期临床试验 (OAA)在轻度痴呆的AD患者中（NCT 02593318），其显示默认模式网络脑增加 通过18FDG-PET测定葡萄糖利用率，并在磁共振成像上增加顶叶和额顶叶还原型谷胱甘肽 核磁共振波谱（MRS）扫描。然而，仅在2g/天的最高剂量下观察到增强。 我们已经开发了新的前药，它将联合收割机OAA与我们提出的其他生物能分子结合起来 将提高大脑中的酮体和丙酮酸水平，协同增加大脑代谢。要求1 将检验我们的假设，即OAA和β-羟基丁酸酯（BHB）或丙二醇（PG）的前药可以增加 可利用的酮体和丙酮酸水平，并影响脑代谢。AIM 2将进一步验证这一点 在转基因小鼠中具有淀粉样蛋白斑块的快速积累（5xFAD）的假设。我们将进一步核实 老年野生型小鼠的活动，更准确地概括了整个身体（因此大脑）下降， 线粒体功能和酮体和葡萄糖代谢失衡。 总之，生物能量医学，即年龄诱导的线粒体功能障碍的纠正，是一种有效的治疗方法。 AD治疗方法与当前的临床方法有根本不同。我们的生物学研究 这里提出的建议可以表明，有一个坚定的理由来开发新的临床药物，利用 多种生物能量机制，以减少脑淀粉样变性和年龄相关的脑代谢下降- 刺激生物能量制药方法的发展。