Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
Sci Rep. 2018 Feb 19;8(1):3301. doi: 10.1038/s41598-018-20162-1.
Chronic cerebral hypoperfusion (CCH) plays an insidious role in the development of cognitive impairment. Considerable evidence suggests that Diabetes Mellitus (DM) as a vascular risk factor may exacerbate CCH and is closely related to cognitive decline. Dysregulation of autophagy is known to be associated with the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. To elucidate the role of autophagy in CCH- and/or DM-related pathogenesis, mouse neuroblastoma Neuro-2a cells were exposed to hypoxia and/or high glucose for 48 h, mimicking CCH complicated with DM pathologies. Chronic hypoxia reduced cell proliferation and increased levels of cleaved caspase-3, whereas high glucose had no obvious synergistic toxic effect. Accumulation of autophagic vacuoles under hypoxia may be due to both autophagy impairment and induction, with the former accounting for Neuro-2a cell death. Additionally, aberrant accumulation of mitochondria in Neuro-2a cells may be attributed to insufficient BNIP3-mediated mitophagy due to poor interaction between BNIP3 and LC3-II. Despite the lack of a significant cytotoxic effect of high glucose under our experimental conditions, our data indicated for the first time that impaired autophagy degradation and inefficient BNIP3-mediated mitophagy may constitute mechanisms underlying neuronal cell damage during chronic hypoxia.
慢性脑灌注不足（CCH）在认知障碍的发展中起着隐匿的作用。大量证据表明，糖尿病（DM）作为血管危险因素可能会加重 CCH，并与认知能力下降密切相关。自噬的失调与阿尔茨海默病等神经退行性疾病的发病机制有关。为了阐明自噬在 CCH 和/或 DM 相关发病机制中的作用，将小鼠神经母细胞瘤 Neuro-2a 细胞暴露于缺氧和/或高葡萄糖 48 小时，模拟 CCH 合并 DM 病理。慢性缺氧降低了细胞增殖并增加了 cleaved caspase-3 的水平，而高葡萄糖没有明显的协同毒性作用。缺氧下自噬小体的积累可能是由于自噬受损和诱导，前者导致 Neuro-2a 细胞死亡。此外，Neuro-2a 细胞中线粒体的异常积累可能归因于 BNIP3 与 LC3-II 之间相互作用不足导致 BNIP3 介导的线粒体自噬不足。尽管在我们的实验条件下高葡萄糖没有明显的细胞毒性作用，但我们的数据首次表明，自噬降解受损和 BNIP3 介导的线粒体自噬效率低下可能是慢性缺氧期间神经元细胞损伤的机制。
