Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease.
Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease.
复制标题
线粒体生物合成受损会导致阿尔茨海默病中的线粒体功能障碍。
DOI：
10.1111/j.1471-4159.2011.07581.x
复制
发表时间：
2012-02
影响因子：
4.7
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Sheng B;Wang X;Su B;Lee HG;Casadesus G;Perry G;Zhu X
线粒体功能障碍是阿尔茨海默病（AD）脑的一个显著特征。我们先前的研究表明，在AD患者脑中的易感海马神经元和过表达FAD引起的APP突变体（APPswe）的M17细胞中，线粒体数量减少。在目前的研究中，我们调查了线粒体生物发生的改变是否有助于AD的线粒体异常。线粒体生物合成受PGC-1α-NRF-TFAM通路调控。AD海马组织和APPswe M17细胞中PGC-1α、NRF 1、NRF 2和TFAM的表达水平均显著降低，提示线粒体生物合成减少。事实上，APPswe M17细胞表现出线粒体DNA/核DNA比率降低，与ATP含量降低和细胞色素C氧化酶活性降低相关。重要的是，PGC-1α的过表达可以完全挽救，而PGC-1α的敲低可以加剧APPswe M17细胞中受损的线粒体生物合成和线粒体缺陷，这表明线粒体生物合成的减少可能与APPswe诱导的线粒体缺陷有关。我们进一步证明cAMP可以剂量依赖性地挽救APPswe M17细胞中p-CREB和PGC-1α表达的降低，PKA抑制剂H89可以抑制cAMP的作用，提示PKA/CREB通路在APPswe M17细胞中PGC-1α表达的调控中起重要作用。总的来说，我们的研究表明，受损的线粒体生物合成可能有助于AD中的线粒体功能障碍。
Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells overexpressing FAD-causing APP mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the PGC-1α-NRF-TFAM pathway. Expression levels of PGC-1α, NRF 1, NRF 2, and TFAM were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, overexpression of PGC-1α could completely rescue while knockdown of PGC-1α could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe-induced mitochondrial deficits. We further demonstrated that reduced expression of p-CREB and PGC-1α in APPswe M17 cells could be rescued by cAMP in a dose-dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC-1α expression in APPswe M17 cells. Overall, our study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD.
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影响因子：
3.5
作者：
Manczak, M;Park, BS;Reddy, PH
通讯作者：
Reddy, PH
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
影响因子：
5
作者：
de la Monte, SM;Luong, T;Wands, JR
通讯作者：
Wands, JR
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
DOI：
10.1073/pnas.0806192105
发表时间：
2008-09-02
影响因子：
11.1
作者：
Petersen, Camilla A. Hansson;Alikhani, Nyosha;Ankarcrona, Maria
通讯作者：
Ankarcrona, Maria