Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease

降低线粒体 ATP 合酶活性可延缓衰老和阿尔茨海默病

• 批准号: 10653496
• 负责人: Michael Petrascheck
• 金额: $ 33.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653496
• 关键词: 3-Dimensional; ATP Synthesis Pathway; Acetyl Coenzyme A; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animals; Area; Award; Behavioral; Brain; Caenorhabditis elegans; Cerebellum; Complex; Crista ampullaris; Data; Deterioration; Development; Dimerization; Electroencephalography; Electron Microscopy; Electrophysiology (science); Elements; Energy Metabolism; Epigenetic Process; Etiology; F1F0-ATP synthase; Face; Funding; Gene Expression; Grant; Hippocampus (Brain); Histology; Image; Inner mitochondrial membrane; Life; Link; Location; Longevity; Measures; Membrane; Memory; Methods; Microscopy; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modernization; Mus; Myelin; Myelin Sheath; Nerve; Nerve Degeneration; Neurons; Oxidative Stress; Parents; Plant Resins; Research; Role; Scanning; Scanning Electron Microscopy; Scientist; Senile Plaques; Structure; Subcellular structure; Surface; Synapses; Synaptic Vesicles; Technology; Thick; Three-dimensional analysis; Tissues; Toxic effect; Wild Type Mouse; Work; X ray microscopy; aged; base; brain tissue; chromatin remodeling; cognitive ability; cognitive performance; cognitive testing; cohort; connectome; design; drug action; drug candidate; druggable target; improved; inhibitor; lipid metabolism; microscopic imaging; mitochondrial metabolism; multimodality; new technology; parent grant; preservation; protein misfolding; reconstruction; synaptic function; transcriptome sequencing

Project Summary The initiative behind RFA-AG-20-013 was designed to understand the role of aging in the development and etiology of Alzheimer's disease (AD) and related dementias (ADRD). Our work shows that the F1F0-ATP synthase, the mitochondrial complex responsible for ATP synthesis, is a core component of the mechanisms linking aging to ADRD. We found that the experimental Alzheimer's drug candidate J147 targets the F1 subunit of ATP synthase to exert geroprotective and neuroprotective effects. Our most recent data, obtained under this grant, shows that J147 robustly extends lifespan in C. elegans via chromatin remodeling in neurons. Our data further suggest that J147 extends lifespan in C57BL6 mice, remodels lipid metabolism, and shows signs of improving cognitive performance in very old animals (28 months of age). These additional data are consistent with our central hypothesis that mitochondria are a pivotal link between aging and ADRD that is druggable. Mitochondria control synaptic gene expression via epigenetics and are subject to deterioration by age-associated toxicities such as protein misfolding or oxidative stress. Treatment with J147 stabilizes mitochondria against age- associated toxicities and thus extends lifespan and protects from neurodegeneration by allowing the mitochondria to maintain control of synapse-related gene expression. For this supplement, we ask for the funds to extend specific Aim 1 in the parent application which determines how protecting mitochondrial function preserves and restores synapse function in aged mice. We propose to determine how protecting mitochondria by treatment with J147 preserves or improves mitochondrial and synapse integrity in very old (28 months) wild-type C57BL6 mice using cutting-edge 3-dimensional electron microscopy. We will engage the National Center for Microscopy and Imaging Research to generate ultrastructures of mitochondria and synapses using multi-scale - multi-modal quantitative 3D microscopies, new technologies that became available since we submitted the original award. These advanced EM methods allow quantitative comparisons of tissue changes, such as amyloid plaque sizes, locations, and numbers - as well as quantitative analysis of cellular and sub-cellular elements like mitochondria or synaptic vesicles predicted to be influenced by the main action of J147 as an ATP synthase inhibitor. Our preliminary data also show an interesting thickening of the myelin sheath in very old (28 months) J147 treated animals that is most likely associated with the effect of J147 on lipid metabolism.

项目概要 RFA-AG-20-013 背后的倡议旨在了解衰老在发育和发育中的作用。 阿尔茨海默病（AD）和相关痴呆（ADRD）的病因学。我们的工作表明 F1F0-ATP 合成酶是负责 ATP 合成的线粒体复合物，是该机制的核心组成部分 将衰老与 ADRD 联系起来。我们发现实验性阿尔茨海默病候选药物 J147 靶向 F1 亚基 ATP合酶发挥老年保护和神经保护作用。我们根据此获得的最新数据 授予，表明 J147 通过神经元染色质重塑有力地延长了秀丽隐杆线虫的寿命。我们的数据 进一步表明 J147 延长了 C57BL6 小鼠的寿命，重塑脂质代谢，并显示出 提高高龄动物（28 个月大）的认知能力。这些附加数据是一致的 我们的中心假设是线粒体是衰老和 ADRD 之间的关键联系，并且可以通过药物治疗。 线粒体通过表观遗传学控制突触基因表达，并会因年龄相关而恶化 毒性，例如蛋白质错误折叠或氧化应激。 J147 治疗可稳定线粒体，对抗年龄增长 相关的毒性，从而延长寿命并通过允许 线粒体维持突触相关基因表达的控制。 对于此补充，我们要求资金用于扩展父申请中的具体目标 1，该目标确定 保护线粒体功能如何保护和恢复老年小鼠的突触功能。我们建议 确定通过 J147 治疗来保护线粒体如何保留或改善线粒体和突触 使用尖端 3 维电子显微镜观察高龄（28 个月）野生型 C57BL6 小鼠的完整性。 我们将与国家显微镜和成像研究中心合作，生成以下超微结构： 使用多尺度-多模态定量 3D 显微镜、新技术来观察线粒体和突触 自我们提交原始奖项后即可使用。这些先进的 EM 方法可以定量 组织变化的比较，例如淀粉样斑块的大小、位置和数量，以及定量 分析预计会受到影响的细胞和亚细胞元素，如线粒体或突触小泡 J147 作为 ATP 合酶抑制剂的主要作用。我们的初步数据还显示出有趣的增厚现象 在非常老（28 个月）的 J147 治疗动物中，髓鞘的变化很可能与 J147 对脂质代谢的影响。