Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death.
Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death.
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DOI：
10.1371/journal.pone.0034929
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mook-Jung I
中科院分区：
文献类型：
--
作者：
Cha MY;Han SH;Son SM;Hong HS;Choi YJ;Byun J;Mook-Jung I
线粒体是最为人所知的细胞内必需细胞器，负责维持细胞生存所需的稳态，但它们也与包括阿尔茨海默病(AD)在内的各种疾病相关。A-淀粉样蛋白(A-β，A-β)是AD发病机制中的关键分子，在AD发病过程中线粒体异常的意义日益突出。神经细胞暴露于Aβ会损害线粒体的动力学和功能。此外，在AD脑中还检测到线粒体Aβ的积聚。然而，Aβ如何影响线粒体功能的潜在机制尚不清楚，线粒体Aβ积聚继而导致线粒体功能障碍是否直接导致神经元毒性也是值得怀疑的。这项研究表明，外源性Aβ1-42处理小鼠的海马细胞系(特别是HT22细胞)时，会导致线粒体在形态和功能上的有害变化。一种网状蛋白介导的内吞阻断剂挽救了外源性Aβ1-42介导的线粒体功能障碍。此外，Aβ1-42结合线粒体靶向序列在HT22细胞中的线粒体靶向蓄积引起了与APP/PS AD小鼠模型和外源性Aβ1-42处理的HT22细胞相同的线粒体形态变化。此外，在线粒体特异的Aβ1-42积累模型中显示了随后的线粒体功能障碍，这被证明与外源Aβ1-42处理的HT22细胞引起的线粒体损伤没有区别。最后，线粒体靶向Aβ1-42的积聚直接诱导了细胞毒性，它模拟了外源Aβ1-42处理的HT22细胞的凋亡过程。综上所述，这些结果表明，线粒体靶向的Aβ1-42积聚是Aβ介导的线粒体损伤的充要条件，并直接导致细胞死亡，而不是伴随着Aβ介导的其他信号改变。
Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ1–42 treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ1–42-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ1–42 in HT22 cells using Aβ1–42 with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ1–42-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ1–42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ1–42-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ1–42 accumulation, which mimics the apoptosis process in exogenous Aβ1–42-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ1–42 accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.
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DOI：
10.1016/0925-4439(95)00038-6
发表时间：
1995-05-24
影响因子：
6.2
作者：
MIZUNO, Y;IKEBE, S;OZAWA, T
通讯作者：
OZAWA, T
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
影响因子：
9
作者：
通讯作者：
--
DOI：
10.3233/jad-2010-100564
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Manczak M;Mao P;Calkins MJ;Cornea A;Reddy AP;Murphy MP;Szeto HH;Park B;Reddy PH
通讯作者：
Reddy PH
DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu