Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons.
Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons.
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DOI：
10.3233/jad-2010-100564
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Reddy PH
中科院分区：
文献类型：
--
作者：
Manczak M;Mao P;Calkins MJ;Cornea A;Reddy AP;Murphy MP;Szeto HH;Park B;Reddy PH
阿尔茨海默病(AD)是一种以记忆和认知功能进行性下降为特征的进行性神经退行性疾病。尽管在了解AD的疾病进展和治疗方面已经取得了巨大的进步，但我们仍然没有能够减缓其进展的药物。本研究的目的是研究线粒体靶向抗氧化剂MitoQ和SS31以及抗衰老药物白藜芦醇对阿尔茨海默病(AD)小鼠模型(Tg2576系)神经元和与淀粉样β蛋白(Aβ)多肽孵育的小鼠神经母细胞瘤(N2a)细胞的影响。应用电子显微镜、共聚焦显微镜、基因表达分析和生化方法，研究了用Aβ孵育N2a细胞后，经MitoQ、SS31和白藜芦醇处理后，N2a细胞线粒体的结构和功能以及突起的生长。在仅与Aβ孵育的N2a细胞中，我们发现线粒体分裂基因的表达增加，融合基因的表达减少，内源性细胞保护性抗氧化酶--过氧化还蛋白的表达也减少。与Aβ孵育的N2a细胞的电子显微镜显示线粒体数量显著增加，表明Aβ使线粒体碎裂。生化分析显示线粒体功能存在缺陷。在Aβ孵育的N2a细胞中，突起生长明显减少，表明Aβ影响突起生长。而在N2a细胞中，加入Aβ后，线粒体结构基因和过氧化还蛋白的异常表达被阻止，线粒体功能正常，线粒体完整，突起生长明显增加。在淀粉样β前体蛋白(AβPP)转基因小鼠的原代神经元中，经MitoQ和SS31处理后，突起生长显著增加，亲环素D表达显著降低。这些结果表明，MTA、MitoQ和SS31可预防线粒体A-β毒性，这为研究MitoQ和SS31作为治疗AD患者的潜在药物奠定了基础。
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by progressive decline of memory and cognitive functions. Despite tremendous progress that has been made in understanding disease progression and therapeutics of AD, we still do not have drugs that are capable of slowing its progression. The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants (MTAs) MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model of Alzheimer’s disease (AD) (Tg2576 line) and on mouse neuroblastoma (N2a) cells incubated with the amyloid beta (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function, and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes, and also decreased expression of peroxiredoxins, endogenous cytoprotective antioxidant enzymes. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid beta precursor protein (AβPP) transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that the MTAs, MitoQ and SS31 prevent Aβ toxicity in mitochondria, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.