Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice.
Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice.
复制标题
短暂性脑缺血促进年轻 5xFAD 小鼠的大脑线粒体功能障碍并加剧认知障碍
DOI：
10.1371/journal.pone.0144068
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Du H
中科院分区：
文献类型：
--
作者：
Lu L;Guo L;Gauba E;Tian J;Wang L;Tandon N;Shankar M;Beck SJ;Du Y;Du H
阿尔茨海默病(AD)是一种异质性和多因素的神经系统疾病，其危险因素仍然难以捉摸。最近的研究强调了血管因素在促进AD进展中的作用，并提示缺血事件增加了AD的发生率。然而，将缺血性损伤与AD进展联系起来的详细机制在很大程度上仍不确定。本研究采用双侧颈总动脉短暂阻断的方法，建立了幼龄5xFAD小鼠及其非转基因(非Tg)仔鼠短暂性脑缺血模型。我们发现，短暂性脑缺血显著加重了幼年5xFAD小鼠脑线粒体功能障碍，包括线粒体呼吸障碍、氧化应激以及线粒体融合蛋白水平的抑制，包括视神经萎缩1(OPA1)和丝裂原蛋白2(Mfn2)，导致空间学习和记忆加剧。有趣的是，短暂性脑缺血并没有导致5xFAD小鼠皮质或线粒体淀粉样β(Aβ)1-40或1-42水平的升高。此外，线粒体靶向抗氧化剂MitoTEMPO可抑制线粒体超氧化物歧化水平，显著减轻糖和氧剥夺引起的A-β处理神经元的神经细胞凋亡。因此，对我们结果的最简单解释是，患有AD样线粒体功能障碍的年轻5xFAD小鼠更容易受到短暂性脑缺血的影响；缺血事件可能会加剧痴呆，并通过加剧线粒体功能障碍而恶化AD患者的预后。
Alzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (Aβ)1-40 or 1–42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in Aβ-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction.