Lustbader Joyce W, Cirilli Maurizio, Lin Chang, Xu Hong Wei, Takuma Kazuhiro, Wang Ning, Caspersen Casper, Chen Xi, Pollak Susan, Chaney Michael, Trinchese Fabrizio, Liu Shumin, Gunn-Moore Frank, Lue Lih-Fen, Walker Douglas G, Kuppusamy Periannan, Zewier Zay L, Arancio Ottavio, Stern David, Yan Shirley ShiDu, Wu Hao
Center for Reproductive Sciences and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Science. 2004 Apr 16;304(5669):448-52. doi: 10.1126/science.1091230.
Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.
线粒体功能障碍是阿尔茨海默病（AD）中β-淀粉样蛋白（Aβ）诱导的神经元毒性的一个标志。在此，我们证明Aβ结合乙醇脱氢酶（ABAD）是从Aβ到线粒体毒性的直接分子联系。Aβ与AD患者和转基因小鼠线粒体中的ABAD相互作用。Aβ结合的ABAD的晶体结构显示活性位点有显著变形，阻止了烟酰胺腺嘌呤二核苷酸（NAD）的结合。一种ABAD肽特异性抑制ABAD-Aβ相互作用，并抑制Aβ诱导的神经元凋亡和自由基生成。在富含Aβ的环境中过表达ABAD的转基因小鼠表现出过度的神经元氧化应激和记忆受损。这些数据表明ABAD-Aβ相互作用可能是AD的一个治疗靶点。
