Exercise-Induced Mitophagy In Hippocampal Neurons Against AD

摘要 阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，无法治愈，影响着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脑内的积累 中枢神经系统是一种早期的中枢病理。功能失调产生的活性氧物种(ROS) 线粒体会对蛋白质、脂质和DNA造成氧化损伤，并加剧 淀粉样蛋白(Aβ，Aβ)积聚和牛磺酸蛋白过度磷酸化的恶性循环。形成鲜明对比的是， 耐力运动(如跑步)或抵抗力运动(如举重)具有显著的预防和 对阿尔茨海默病的治疗效果。然而，人们对其潜在的机制知之甚少。AMP依赖 蛋白激酶(AMPK)是一种主要的能量感应器，已成为一种有前途的调节剂。 锻炼的好处。AMPK主要在海马区的神经元中表达，其活性在 AD的动物模型。重要的是，耐力运动通过减少Aβ的沉积恢复AMPK的活性 恢复了空间学习和记忆。一种有希望但未经测试的机制是运动诱导的有丝分裂， AMPK及其下游调控下损伤/功能障碍线粒体的选择性降解 UNC-51样自噬激活激酶(Ulk1)，导致线粒体质量改善。我们假设 耐力和/或抵抗运动促进AMPK-Ulk1的激活和有丝分裂，从而去除 成年海马神经元线粒体损伤/功能障碍与神经退变的预防 AD时认知功能下降。为了检验这一假设，我们提出： 1.确定运动介导的AD保护作用是否需要AMPK-Ulk1的激活。 2.确定AMPK的激活是否足以预防AD。 拟议的研究是以假设为导向的，并得到了之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以及线粒体 报道小鼠，阐述运动诱导的有丝分裂吞噬的重要性和调节抗AD。调查结果 将为开发针对AMPK和有丝分裂吞噬的有效治疗AD铺平道路。

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.