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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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病（AD）和相关痴呆症（ADRD）的最大危险因素。然而，将衰老机制与 ADRD 联系起来的潜在分子机制尚不清楚。发展老年保护剂，针对衰老的药物，可用于治疗 ADRD，我们开发了一种以神经为中心的药物老年科学平台，用于识别老年神经保护剂 (GNP)、延长寿命的老年保护剂和同时保护神经元免受多种年龄相关毒性的影响。 GNPs应该是理想的治疗方法对于 ADRD。仅延长寿命而不治疗痴呆症只会延缓疾病的发生，甚至延长寿命疾病持续时间，从而恶化 ADRD 问题，这是寿命不断延长的结果。我们提出了 GNP J147 的原理证明，并表明它可以延长寿命、防止记忆丧失，甚至当 20-24 个月大的野生型或有症状的 APPswe 小鼠开始治疗时，可恢复记忆。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毒性应激合酶活性，将能量代谢转向糖酵解，并伴随着乙酰辅酶A的积累。乙酰辅酶A的积累导致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 - 和从而导致功能衰退。在下面的提案中，我们将通过进行详细测试该模型老年野生型小鼠和两种小鼠模型的神经病理学、电生理学和行为测定 ADRD。我们证明这些效应在进化上是保守的并且降低了 ATP 合酶活性延长小家鼠、黑腹果蝇和线虫的寿命。 ATP合酶和年龄- 突触基因的相关转录漂移在进化上从小肌到秀丽隐杆线虫都是保守的我们将使用秀丽隐杆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及其对线粒体损伤的反应。我们将验证已识别因素的作用控制初级神经元、老年野生型小鼠和小鼠模型突触启动子上的染色质 ADRD。最后，我们将扩展我们的 GNP 概念，以分析由干预测试计划（ITP），以评估其保护神经元免受不同年龄相关毒性的能力，以及确定具有互补保护作用的老年保护剂组合。因为 ADRD 是具有多种病理学方面的复杂疾病，不可能通过单一药物来解决，我们预测合理设计的老年保护剂组合将优于单个老年保护剂。这些研究将共同深入了解衰老和 ADRD 如何损害突触功能以及如何通过单一 GNP 或合理 GNP 组合的治疗来解决这个问题。