Mitochondria targeting for Alzheimer's Disease

项目总结 能量代谢降低是阿尔茨海默病(AD)患者大脑的一个不变特征，但 具体使用药物策略来操纵大脑中的能量代谢仍然相对较少。 未经测试。我们已经开发出一种新的治疗AD的方法，它利用基本的生化原理 例如质量作用定律，并另外利用氧化还原比(特别是NAD/NADH耦合) 获取一些生物能量通量。我们的主要假设是增强大脑呼吸流量，糖酵解 通量，或两者兼而有之，将使AD患者受益。我们已经创造了一种新药，可以诱导一种近生酮状态，我们 提出会增强大脑新陈代谢，减少淀粉样蛋白病理改变。 这个探索性R21提案目的是检验我们的假设，即我们的新的“生物能量”药物 该方法将提高脑能量利用率并减少老年野生型和老年性淀粉样斑块的形成 转基因小鼠。我们最近完成了生物能量化合物草酰乙酸酯的1B期临床试验 (OAA)AD患者的轻度痴呆(NCT02593318)，显示默认模式网络脑增加 18FDG-PET对葡萄糖的利用和顶叶和额叶还原型谷胱甘肽的增加 磁共振波谱(MRS)扫描。然而，只有在2g/天的最高剂量时才能看到增强。 我们已经开发了新的前药，将OAA与我们提出的额外生物能量分子结合在一起 会提高大脑中的酮体和丙酮酸水平，协同促进大脑新陈代谢。目标1 将检验我们的假设，即老年再生障碍性贫血和β-羟基丁酸酯(BHB)或丙二醇(PG)的前体药物可以增加 可利用的酮体和丙酮酸水平分别影响大脑新陈代谢。AIM 2将进一步测试这一点 快速积累淀粉样斑块的转基因小鼠的假说(5xFAD)。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(从而大脑)的活动在 酮体和葡萄糖代谢中线粒体的功能和失衡。 总之，生物能量医学，即纠正年龄引起的线粒体功能障碍，是一种 阿尔茨海默病的治疗方法从根本上不同于目前的临床方法。我们的生物学研究 在这里提出可能表明有一个坚实的理由来开发新的临床药物，利用 多种生物能量机制减少脑淀粉样变性和与年龄相关的脑代谢下降- 促进生物能制药方法的发展。

PROJECT SUMMARY 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.