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: 10618893
• 负责人: Michael Petrascheck
• 金额: $ 91.1万
• 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/10618893
• 关键词: ATP Synthesis Pathway; Acarbose; Acceleration; Acetyl Coenzyme A; Acetylation; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Behavioral Assay; Biological Assay; Brain; Brain Pathology; Caenorhabditis elegans; Cell Culture Techniques; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Cognitive deficits; Complex; Data; Dementia; Dendritic Spines; Deterioration; Disease; Drug Targeting; Electrophysiology (science); Energy Metabolism; Epigenetic Process; Estradiol; F1F0-ATP synthase; Gene Expression; Genes; Genetic Transcription; Geroscience; Glycolysis; Goals; Histone Acetylation; Homeostasis; Human; Impairment; Individual; Intervention; Lead; Link; Long-Term Potentiation; Longevity; Memory; Memory Loss; Metabolism; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modeling; Molecular; Mus; Neurons; Onset of illness; Oxidative Stress; Pathologic; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Process; Production; Publishing; RNA Interference; Rodent Model; Role; Sirolimus; Slice; Stress; Synapses; Synaptosomes; Testing; Therapeutic; Toxic effect; Wild Type Mouse; Work; aged; alpha ketoglutarate; chromatin remodeling; cognitive function; drug candidate; fly; functional decline; illness length; improved; insight; mouse model; neuropathology; neuroprotection; preservation; prevent; programs; promoter; protective effect; proteotoxicity; rational design; response; synaptic function; synergism; tau Proteins

ABSTRACT Aging is the biggest risk factor for Alzheimer's disease (AD) and related dementias (ADRD). However, the underlying molecular mechanism that link mechanisms of aging to ADRDs are unknown. To develop geroprotectors, drugs that target aging and could be used to treat ADRDs we developed a neuro-centric geroscience platform to identify Gero-Neuro-Protectors (GNP), geroprotectors that extend lifespan and simultaneously protect neurons from multiple age associated toxicities. GNPs should make ideal treatments for ADRDs. Increasing lifespan alone, without treating dementia, will only delay disease onset or even prolong disease duration, and thus worsen the ADRD problem, which is the consequence of ever increasing lifespans. We present a proof of principle GNP, J147 and show that it extends lifespan, prevents memory loss, and even restores memory when treatment is initiated in 20-24 month old wild type or symptomatic APPswe mice. We propose a testable model in which J147 protects neurons from ongoing proteotoxic stress by lowering ATP synthase activity, shifting energy metabolism towards glycolysis accompanied by accumulation of acetyl-CoA. Accumulating acetyl-CoA leads to increased H3K9 histone acetylation and protects synapse related gene expression from transcriptional drift -the age-associated deterioration of transcriptional programs- and consequently from functional decline. In the following proposal we will test this model in detail by conducting neuropathology, electrophysiology and behavioral assays in aged wild type mice and two mouse models of ADRD. We show that these effects are evolutionarily conserved and that lowering ATP synthase activity extends lifespan in M. musculus, D. melanogaster and C. elegans. As both, ATP synthase and the age- associated transcriptional drift of synaptic genes are evolutionarily conserved from M. musculus to C. elegans we will use C. elegans to identify the chromatin remodeling factor that controls synapse related gene expression in aging and how it respond to mitochondrial insults. We will validate the role of the identified factor in controlling chromatin on synaptic promoters in primary neurons, aged wild type mice and mouse models of ADRD. Finally, we will expand our GNP concept to profile geroprotective compounds identified by the intervention testing program (ITP) for their ability to protect neurons from different age-associated toxicities and to identify combinations of geroprotectors that are complementary in their protective effects. Because ADRDs are complex diseases with multiple pathological aspects that are unlikely to be addressable by a single drug, we predict rationally designed combinations of geroprotectors to outperform individual geroprotectors. Together these studies will provide deep insights into how aging and ADRDs compromise synapse function and how this can be addressed by treatment with single GNPs or rational GNP combinations.

摘要 衰老是阿尔茨海默病(AD)和相关痴呆(ADRD)的最大风险因素。然而， 将衰老机制与ADRD联系起来的潜在分子机制尚不清楚。发展，发展 基因保护剂，针对衰老的药物，可用于治疗ADRDS我们开发了一种以神经为中心的 老年科学平台，用于识别老年神经保护器(GNP)、延长寿命和 同时保护神经元免受多种年龄相关的毒性。GNP应提供理想的治疗方案 用于ADRDS。单独延长寿命，而不治疗痴呆症，只会推迟疾病的发病，甚至延长 疾病持续时间延长，从而使ADRD问题恶化，而ADRD问题是寿命不断延长的结果。 我们给出了一个GNP原理的证明，J147，并表明它延长了寿命，防止了记忆损失，甚至 在20-24个月大的野生型或有症状的APPswe小鼠开始治疗时恢复记忆。我们 提出一个可测试的模型，在该模型中，J147通过降低ATP来保护神经元免受持续的蛋白毒性应激 合酶活性，能量代谢向糖酵解转移，伴随着乙酰辅酶A的积累。 乙酰辅酶A积聚导致H3K9组蛋白乙酰化增加并保护突触相关基因 转录漂移的表达--转录程序的年龄相关恶化--以及 因此，从功能衰退。在下面的提案中，我们将通过执行以下操作来详细测试该模型 老龄野生型小鼠和两种小鼠模型的神经病理、电生理和行为分析 阿德勒。我们发现，这些影响在进化上是保守的，而且降低ATP合成酶活性 延长肌肉分枝杆菌、黑腹分枝杆菌和线虫的寿命。作为两者，ATP合成酶和年龄- 从肌肉分枝杆菌到线虫，突触基因的相关转录漂移在进化上是保守的 我们将使用线虫来鉴定控制突触相关基因的染色质重塑因子 衰老过程中的表达以及它对线粒体侮辱的反应。我们将验证确定的因素的作用 在控制染色质对初级神经元突触启动子的影响方面，衰老野生型小鼠和 阿德勒。最后，我们将扩展我们的GNP概念，以描述由 干预测试计划(ITP)的能力，以保护神经元免受不同年龄相关的毒性和 以确定在保护效果上互补的齿轮保护剂的组合。因为ADRDS 是具有多种病理方面的复杂疾病，不太可能通过一种药物来解决， 我们预测，合理设计的齿轮保护器组合的性能将超过单独的齿轮保护器。 总而言之，这些研究将为衰老和ADRD如何损害突触功能提供深刻的见解 以及如何通过单一GNP或合理的GNP组合来解决这一问题。