毒性
线粒体
氧化应激
转基因小鼠
转基因
NAD+激酶
烟酰胺腺嘌呤二核苷酸
化学
细胞生物学
神经毒性
药理学
生物
生物化学
酶
基因
有机化学
作者
Joyce W. Lustbader,Maurizio Cirilli,Chang Lin,Hongwei Xu,Kazuhiro Takuma,Ning Wang,Casper Caspersen,Xi Chen,Susan Pollak,Michael O. Chaney,Fabrizio Trinchese,Shumin Liu,Frank J. Gunn-Moore,Lih‐Fen Lue,Douglas G. Walker,Periannan Kuppusamy,Zay L. Zewier,Ottavio Arancio,David M. Stern,Shirley ShiDu Yan,Hao Wu
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2004-04-16
卷期号:304 (5669): 448-452
被引量:1182
标识
DOI:10.1126/science.1091230
摘要
Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ)–induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aβ interaction and suppresses Aβ-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aβ-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aβ interaction may be a therapeutic target in AD.
科研通智能强力驱动
Strongly Powered by AbleSci AI