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.

中文翻译：

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PINK1 信号传导可挽救阿尔茨海默病中的淀粉样蛋白病理和线粒体功能障碍


线粒体功能障碍和突触损伤是阿尔茨海默病大脑的早期病理特征。阿尔茨海默氏病的记忆障碍是大脑病理的一种表现，例如淀粉样β肽的积累和线粒体损伤。阿尔茨海默病的潜在致病机制和有效的疾病缓解疗法仍然难以捉摸。在这里，我们首次证明 PTEN 诱导的推定激酶 1 (PINK1) 表达减少与阿尔茨海默病病理学相关。恢复神经元 PINK1 功能可显着降低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小鼠更早地出现脑淀粉样蛋白-β积累、线粒体异常、学习和记忆障碍以及突触可塑性增强。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，从而促进受损线粒体的清除，从而减轻阿尔茨海默病小鼠中淀粉样蛋白-β 诱导的突触损失和认知能力下降。 PINK1 活性的丧失或 PINK1 介导的信号传导（OPTN 或 NDP52）的阻断无法逆转淀粉样蛋白-β 诱导的有害影响。我们的研究结果强调了一种新机制，通过该机制，PINK1 依赖性信号传导以需要激活自噬受体 OPTN 或 NDP52 的方式促进淀粉样蛋白病理学和淀粉样蛋白-β 介导的线粒体和突触功能障碍的挽救。因此，PINK1 的激活可能代表了对抗阿尔茨海默病的新治疗途径。