Skeletal muscle mitochondrial abnormalities in Alzheimer's Disease

摘要/项目摘要 新出现的证据表明，线粒体功能障碍和能量代谢受损在 阿尔茨海默病(AD)的发展。我们小组之前曾报道线粒体功能降低 从AD患者血液中分离的血小板和由 AD患者的线粒体DNA。此外，阿尔茨海默病的早期症状之一是 大脑，进一步证明线粒体功能障碍。骨骼肌线粒体在整个骨骼肌中起着至关重要的作用 身体有氧能力(VO2峰值)，是慢性病和死亡风险的有力预测指标。 骨骼肌线粒体功能障碍也与全身胰岛素抵抗有关，后者有 成为AD的风险因素。为了支持这些概念，我们之前已经表明，AD患者 与非痴呆症(ND)相比，有氧能力和胰岛素敏感性都有所降低 年龄和体重相似的受试者，强烈表明AD患者也有骨骼肌 线粒体功能障碍。AD患者骨骼肌线粒体功能障碍的潜在原因是 不清楚，但可能与不活跃的生活方式(长期不活动和久坐不动的生活方式)有关，这是 越来越多地与认知能力降低和阿尔茨海默病风险有关，并加速骨骼肌线粒体 随着年龄的增长而出现的功能障碍。此外，遗传学可能在线粒体功能障碍中起作用。 发现于公元后。载脂蛋白E4(apoEε4)携带者患散发性AD和动物的风险最大 模型提示载脂蛋白Eε4通过病理域损害线粒体呼吸功能 互动。因此，生活方式和遗传因素都有可能影响骨骼肌。 AD患者的线粒体功能，但这还没有被检测到。为了解决这一知识差距，我们 将检测骨骼肌线粒体含量、-酶活性、-呼吸量和-H202 与年龄和性别匹配的ND受试者相比，AD患者的骨骼肌活检组织中的放射性物质。 为了检验基因的作用，我们将招募载脂蛋白Eε4携带者或非携带者。 AD组和ND组(每组各一半)。为了检验生活方式的作用，我们将测量有氧运动 容量(VO2峰值)以及所有受试者的日常体力活动和久坐行为。第一个目标是测试 如果骨骼肌线粒体功能和全身有氧能力在AD和 APOEε4载体与ND和非APOEε4载体的比较。第二个目标是对线粒体进行排序 功能和有氧能力功能取决于AD状态和基因。这项新颖的研究 研究非大脑靶点如何通过生活方式和/或遗传因素驱动AD易感性，以及 指出骨骼肌线粒体是未来预防阿尔茨海默病的治疗目标。

Abstract/Project Summary Emerging evidence suggests mitochondrial dysfunction and impaired energy metabolism play a role in the development of Alzheimer's disease (AD). Our group previously reported reduced mitochondrial function in platelets isolated from blood of AD patients and in cytoplasmic hybrid cell lines generated with mitochondrial DNA from AD patients. Moreover, one of the early signs of AD is hypo-metabolism in the brain, further proof of mitochondrial dysfunction. Skeletal muscle mitochondria play a critical role in whole body aerobic capacity (VO2 peak), a powerful predictor of chronic disease and mortality risk. Mitochondrial dysfunction in skeletal muscle is also involved in whole body insulin resistance, which has emerged as a risk factor for AD. In support of these concepts, we have previously shown that AD patients have both reduced aerobic capacity and reduced insulin sensitivity compared to non-demented (ND) subjects of similar age and weight, strongly suggesting that AD patients also have skeletal muscle mitochondrial dysfunction. Potential causes for skeletal muscle mitochondrial dysfunction in AD patients is unclear but could be linked to an inactive lifestyle (chronic inactivity and sedentary lifestyle), which is increasingly linked to reduced cognition and AD risk and also accelerates skeletal muscle mitochondrial dysfunction that occurs with aging. In addition, genetics may play a role in the mitochondrial dysfunction found in AD. Apolipoprotein E4 (APOE ε4) carriers have the greatest risk for sporadic AD and animal models suggest that APOE ε4 impairs mitochondrial respiratory function via a pathological domain interaction. Therefore, it is possible that both lifestyle and genetic factors impact skeletal muscle mitochondrial function in AD patients but this has not been examined. To address this knowledge gap we will examine skeletal muscle mitochondrial-content, -enzyme activity, -respiratory capacity, and -H202 emission in skeletal muscle biopsies obtained from AD compared to age and sex matched ND subjects. To examine the role of genotype, we will recruit subjects that are APOE ε4 carriers or non-carriers in both the AD and ND groups (half of each group). To examine the role of lifestyle we will measure aerobic capacity (VO2 peak) and daily physical activity and sedentary behavior in all subjects. The first aim will test if skeletal muscle mitochondrial function and whole-body aerobic capacity are compromised in AD and in APOE ε4 carriers compared to ND and non-APOE ε4 carriers. The second aim will rank mitochondrial function and aerobic capacity function dependent upon AD status and genotype. This novel study examines how non-brain targets may drive AD susceptibility via lifestyle and/or genetic factors and could point to skeletal muscle mitochondria as a target for future therapies for prevention of AD.