Exercise-Induced Mitophagy In Hippocampal Neurons Against AD

运动诱导的海马神经元线粒体自噬对抗 AD

• 批准号: 10765466
• 负责人: Zhen Yan
• 金额: $ 55.52万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765466
• 关键词: Acute; Address; Adult; Aerobic Exercise; Affect; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid beta-Protein Precursor; Animal Model; Autophagocytosis; Autopsy; Biochemical; Biological Assay; Brain; Brain Diseases; CRISPR/Cas technology; Cells; Central Nervous System; Color; DNA; Data; Development; Diabetes Mellitus; Disease; Excision; Exercise; Foundations; Gene Proteins; Genetic; Genetic Models; Hippocampus; Image; Immunofluorescence Immunologic; Impaired cognition; Injury; J20 mouse; Knock-in Mouse; Learning; Lipids; Mediating; Memory; Metformin; Mitochondria; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathologic; Pathology; Persons; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Power Plants; Preventive; Protein Kinase; Proteins; Publishing; Radial; Reactive Oxygen Species; Regulation; Reporter; Reticulum; Role; Running; Sampling; Solid; Structure; Testing; Therapeutic; Training; Water; Weight; Weight Lifting; Western Blotting; abeta accumulation; abeta deposition; aging population; arm; beta amyloid pathology; cognitive function; drinking water; endurance exercise; exercise training; familial Alzheimer disease; field study; gain of function; hyperphosphorylated tau; improved; loss of function; novel; oxidative damage; prevent; progressive neurodegeneration; resistance exercise; response; sedentary; sensor; tau Proteins; tau-1; therapeutic target; therapeutically effective; transcriptomics

ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disease with no cure that affects >50 millions of people worldwide. Emerging evidence supports that accumulation of damaged/dysfunctional mitochondria in the central nervous system is an early, central pathology. Reactive oxygen species (ROS) produced by dysfunctional mitochondria cause oxidative damages to proteins, lipids and DNA and exacerbate the key pathologies of amyloid-β (Aβ) accumulation and hyperphosphorylation of Tau protein in a vicious cycle. In stark contrast, endurance exercise (i.e., running) or resistance exercise (i.e., weightlifting) have significant preventive and therapeutic impacts on AD. However, the underlying mechanisms are poorly understood. AMP-dependent protein kinase (AMPK), a master energy sensor, has emerged as a promising regulator underlying the superb benefits of exercise. AMPK is primarily expressed in neurons in the hippocampus, and its activity is reduced in animal models of AD. Importantly, endurance exercise restores AMPK activity with reduced Aβ deposition along with restored spatial learning and memory. A promising but untested mechanism is exercise-induced mitophagy, a selective degradation of damaged/dysfunctional mitochondria under the control of AMPK and its downstream unc-51-like autophagy activating kinase (Ulk1), resulting in improved mitochondrial quality. We hypothesize that endurance and/or resistance exercise promotes AMPK-Ulk1 activation and mitophagy, hence removing damaged/dysfunctional mitochondria in adult hippocampal neurons and preventing neurodegeneration and cognitive decline in AD. To test this hypothesis, we propose: 1. To determine whether AMPK-Ulk1 activation is required for exercise-mediated protection against AD. 2. To ascertain whether AMPK activation is sufficient to protect against AD. The proposed studies are hypothesis-driven and supported by previously published and preliminary findings with strong scientific premises. We have also developed unique exercise and genetic models along with mitochondrial reporter mice to address the importance and regulation of exercise-induced mitophagy against AD. The findings will pave the way for developing effective therapeutics targeting AMPK and mitophagy for AD.

摘要 阿尔茨海默病（AD）是一种无法治愈的破坏性神经退行性疾病，影响超过5000万人， 世界各地的人们。新出现的证据支持，受损/功能障碍的线粒体在细胞中的积累， 中枢神经系统是一种早期的中枢病变。活性氧（ROS）由功能失调的 线粒体导致蛋白质、脂质和DNA的氧化损伤，并加剧了 淀粉样蛋白-β（Aβ）积累和Tau蛋白过度磷酸化的恶性循环。与此形成鲜明对比的是， 耐力锻炼（即，跑步）或阻力锻炼（即，举重）具有显著的预防作用， 对AD的治疗效果然而，对潜在的机制知之甚少。amp依赖 蛋白激酶（AMPK），一种主要的能量传感器，已经成为一种有前途的调节剂， 锻炼的好处。AMPK主要在海马神经元中表达，其活性在海马神经元中降低。 AD动物模型重要的是，耐力运动恢复AMPK活性，减少Aβ沉积沿着 恢复了空间学习和记忆一个有希望但未经检验的机制是运动诱导的线粒体自噬， 在AMPK及其下游的控制下选择性降解受损/功能障碍的线粒体 unc-51样自噬激活激酶（Ulk 1），导致线粒体质量改善。我们假设 耐力和/或阻力运动促进AMPK-Ulk 1激活和线粒体自噬，因此去除 成年海马神经元中的线粒体受损/功能障碍和预防神经变性 和认知能力的下降。为了验证这一假设，我们建议： 1.确定AMPK-Ulk 1激活是否是运动介导的抗AD保护所必需的。 2.确定AMPK激活是否足以预防AD。 拟议的研究是假设驱动的，并得到先前发表的初步研究结果的支持， 强大的科学前提。我们还开发了独特的运动和遗传模型，沿着线粒体 报告小鼠，以解决运动诱导的线粒体自噬对AD的重要性和调节。这些发现 将为开发针对AMPK和线粒体自噬的有效治疗AD铺平道路。