PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease
PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease
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DOI：
10.1093/brain/awx258
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发表时间：
2017-12-01
期刊：
影响因子：
14.5
通讯作者：
Yan, Shirley ShiDu
中科院分区：
文献类型：
--
作者：
Du, Fang;Yu, Qing;Yan, Shirley ShiDu
线粒体功能障碍是阿尔茨海默病影响大脑的早期病理特征。Du等人证明，恢复mAPP/ PINK1（-/-）小鼠的PINK1功能可以降低A β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。激活PINK1可能代表了对抗阿尔茨海默病的新治疗途径。线粒体功能障碍和突触损伤是阿尔茨海默病影响大脑的早期病理特征。阿尔茨海默病的记忆障碍是淀粉样肽积累和线粒体损伤等脑病理的表现。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）表达降低与阿尔茨海默病病理相关。恢复神经元PINK1功能显著降低淀粉样蛋白水平、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小鼠在更早的年龄增加了大脑淀粉样蛋白积累、线粒体异常、学习和记忆障碍以及突触可塑性。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）来增强自噬信号，从而促进受损线粒体的清除，从而减轻淀粉样蛋白β诱导的突触丧失和阿尔茨海默病小鼠的认知能力下降。PINK1活性的丧失或PINK1介导的信号传导（OPTN或NDP52）的阻断不能逆转淀粉样蛋白诱导的有害影响。我们的研究结果强调了一种新的机制，通过这种机制，pink1依赖的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和淀粉样蛋白β介导的线粒体和突触功能障碍的修复。因此，激活PINK1可能代表了对抗阿尔茨海默病的新治疗途径。
Mitochondrial dysfunction is an early pathological feature of the Alzheimer's disease-affected brain. Du et al. demonstrate that restoring PINK1 function in mAPP/Pink1(-/-) mice reduces A beta levels, amyloid-associated pathology, oxidative stress, and mitochondrial and synaptic dysfunction. Activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer's disease.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-beta 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-beta levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-beta 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-beta-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-beta-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-beta-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.