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; 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.

抽象的 衰老是阿尔茨海默氏病（AD）和相关痴呆症（ADRD）的最大危险因素。但是， 将衰老机制与ADRD联系起来的基本分子机制尚不清楚。发展 Geroprotector，靶向衰老的药物，可用于治疗ADRD，我们开发了以神经为中心的药物 识别Gero-Neuro Protectors（GNP）的GEROSCIENCE平台，延长寿命和 同时保护神经元免受多年相关毒性的影响。 GNP应该做好理想的治疗 对于adrds。单独增加寿命，而无需治疗痴呆，只会延迟疾病发作甚至延长 疾病持续时间，因此使ADRD问题恶化，这是寿命不断增加的结果。 我们提供了原则GNP，J147的证明，并表明它可以延长寿命，防止记忆丧失，甚至是 在20-24个月大的野生型或有症状的Appswe小鼠中启动治疗时，会恢复记忆。我们 提出了一个可测试的模型，其中J147通过降低ATP保护神经元免受持续的蛋白质毒性应激 合成酶活性，将能量代谢转移到糖酵解伴随着乙酰辅酶A的积累。 累积的乙酰辅酶A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 - 与年龄相关的转录程序恶化 - 和 因此来自功能下降。在以下建议中，我们将通过进行详细测试该模型 老年野生型小鼠的神经病理学，电生理学和行为测定和两种小鼠模型 adrd。我们表明这些影响在进化上是保守的，并且降低了ATP合酶活性 在M. Musculus，D。Melanogaster和C. exemans中延长寿命。同时，ATP合酶和年龄 - 突触基因的相关转录漂移在进化上是从肌肉菌到秀丽隐杆线虫的进化保守的 我们将使用秀丽隐杆线虫来识别控制突触相关基因的染色质重塑因子 衰老中的表达及其对线粒体侮辱的反应。我们将验证确定因素的作用 在原发性神经元中的突触启动子上控制染色质时，老化的野生型小鼠和小鼠模型 adrd。最后，我们将将我们的GNP概念扩展到配置识别的老年保护化合物 干预测试计划（ITP），以保护神经元免受不同年龄相关的毒性和 确定具有保护作用的互补的药物保护剂的组合。因为adrds 是具有多种病理方面的复杂疾病，单一药物不太可能解决， 我们预测，天生保护剂的合理设计的组合对胜过单个Geroprotectors。 这些研究将共同​​提供有关衰老和ADRD如何妥协突触功能的深刻见解 以及如何通过单个GNP或合理的GNP组合来解决这一问题。