ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease

被引:1098
作者
Lustbader, JW
Cirilli, M
Lin, C
Xu, HW
Takuma, K
Wang, N
Caspersen, C
Chen, X
Pollak, S
Chaney, M
Trinchese, F
Liu, SM
Gunn-Moore, F
Lue, LF
Walker, DG
Kuppusamy, P
Zewier, ZL
Arancio, O
Stern, D
Yan, SSD
Wu, H
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Ctr Reprod Sci, New York, NY 10032 USA
[3] Columbia Univ Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA
[5] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA
[6] Harbin Med Univ, Dept Immunol, Harbin 150086, Peoples R China
[7] NYU, Dept Neurol, New York, NY 10003 USA
[8] NYU, Nathan Kline Inst, Dementia Res Ctr, New York, NY 10016 USA
[9] NYU, Dept Psychiat Physiol & Neurosci, New York, NY 10016 USA
[10] Univ St Andrews, Sch Biol, St Andrews KY16 9TS, Fife, Scotland
[11] Sun Hlth Res Inst, Sun City, AZ 85351 USA
[12] Ohio State Univ, David Heart & Lung Res Inst, Columbus, OH 43210 USA
[13] Med Coll Georgia, Deans Off, Augusta, GA 30912 USA
关键词
D O I
10.1126/science.1091230
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:448 / 452
页数:5
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