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- Title
ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
- Authors
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
- Abstract
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.
- Publication
Science (New York, N.Y.), 2004, Vol 304, Issue 5669, p448
- ISSN
1095-9203
- Publication type
Journal Article
- DOI
10.1126/science.1091230