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.

项目摘要 RFA-AG-20-013背后的倡议旨在了解衰老在开发中的作用和 阿尔茨海默氏病（AD）和相关痴呆症（ADRD）的病因。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，是机制的核心组成部分 将老化与ADRD联系起来。我们发现实验性阿尔茨海默氏症的候选药物J147针对F1亚基 ATP合酶发挥细胞保护作用和神经保护作用。我们在此获得的最新数据 格兰特（Grant）表明，J147通过神经元中的染色质重塑在秀丽隐杆线虫中的寿命稳健地延长了寿命。我们的数据 进一步表明J147在C57BL6小鼠中延长了寿命，重塑脂质代谢，并显示出迹象 改善非常古老的动物的认知表现（28个月大）。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，可吸毒。 线粒体控制突触基因表达通过表观遗传学，并且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）。用J147治疗可稳定线粒体与年龄 相关的毒性，从而延长寿命并通过允许 线粒体维持与突触相关基因表达的控制。 对于此补充，我们要求资金在父母申请中扩展特定目标1 保护线粒体功能如何保留并恢复老年小鼠的突触功能。我们建议 确定如何通过用J147蛋白处理或改善线粒体和突触来保护线粒体 使用尖端的3维电子显微镜的非常古老（28个月）的野生型C57BL6小鼠的完整性。 我们将与国家显微镜和成像研究中心互动，以生成 线粒体和突触使用多尺度 - 多模式定量3D显微镜，新技术 自从我们提交原始奖项以来就可以使用。这些高级EM方法允许定量 比较组织变化的比较，例如淀粉样斑块的大小，位置和数字以及定量 分析细胞和亚细胞元素，例如线粒体或突触囊泡被预测的影响 通过J147作为ATP合酶抑制剂的主要作用。我们的初步数据还显示了一个有趣的增厚 在非常古老的（28个月）J147治疗的动物中的髓鞘鞘的影响很可能与 J147关于脂质代谢。