Du Fang, Yu Qing, Yan Shijun, Hu Gang, Lue Lih-Fen, Walker Douglas G, Wu Long, Yan Shi Fang, Tieu Kim, Yan Shirley ShiDu
Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, 66047, USA.
Arizona State University, Tempe, AZ85281, USA.
Brain. 2017 Dec 1;140(12):3233-3251. doi: 10.1093/brain/awx258.
Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease-affected brain. Memory impairment in Alzheimer's disease is a manifestation of brain pathologies such as accumulation of amyloid-β peptide and mitochondrial damage. The underlying pathogenic mechanisms and effective disease-modifying therapies for Alzheimer's disease remain elusive. Here, we demonstrate for the first time that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with Alzheimer's disease pathology. Restoring neuronal PINK1 function strikingly reduces amyloid-β levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-β accumulation, mitochondrial abnormalities, impairments in learning and memory, as well as synaptic plasticity at an earlier age than mAPP mice. Notably, gene therapy-mediated PINK1 overexpression promotes the clearance of damaged mitochondria by augmenting autophagy signalling via activation of autophagy receptors (OPTN and NDP52), thereby alleviating amyloid-β-induced loss of synapses and cognitive decline in Alzheimer's disease mice. Loss of PINK1 activity or blockade of PINK1-mediated signalling (OPTN or NDP52) fails to reverse amyloid-β-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-β-mediated mitochondrial and synaptic dysfunctions in a manner requiring activation of autophagy receptor OPTN or NDP52. Thus, activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer's disease.
线粒体功能障碍和突触损伤是阿尔茨海默病累及大脑的早期病理特征。阿尔茨海默病中的记忆障碍是诸如β淀粉样肽积累和线粒体损伤等脑部病变的一种表现。阿尔茨海默病的潜在致病机制和有效的疾病修饰疗法仍然不明。在此，我们首次证明，PTEN诱导的假定激酶1（PINK1）表达降低与阿尔茨海默病病理相关。恢复神经元PINK1功能可显著降低β淀粉样蛋白水平、淀粉样蛋白相关病理、氧化应激以及线粒体和突触功能障碍。相比之下，PINK1缺陷的mAPP小鼠比mAPP小鼠在更早的年龄就出现脑内β淀粉样蛋白积累增加、线粒体异常、学习和记忆障碍以及突触可塑性受损。值得注意的是，基因治疗介导的PINK1过表达通过激活自噬受体（OPTN和NDP52）增强自噬信号传导，从而促进受损线粒体的清除，进而减轻β淀粉样蛋白诱导的阿尔茨海默病小鼠突触丧失和认知衰退。PINK1活性丧失或PINK1介导的信号传导（OPTN或NDP52）阻断无法逆转β淀粉样蛋白诱导的有害作用。我们的研究结果突出了一种新机制，即PINK1依赖性信号传导通过需要激活自噬受体OPTN或NDP52的方式促进β淀粉样蛋白病理以及β淀粉样蛋白介导的线粒体和突触功能障碍的挽救。因此，激活PINK1可能代表对抗阿尔茨海默病的一条新治疗途径。
