ABAD Directly Links A
to Mitochondrial Toxicity in Alzheimer's Disease
Joyce W. Lustbader,
Maurizio Cirilli,
Chang Lin,
Hong Wei Xu,
Kazuhiro Takuma,
Ning Wang,
Casper Caspersen,
Xi Chen,
Susan Pollak,
Michael Chaney,
Fabrizio Trinchese,
Shumin Liu,
Frank Gunn-Moore,
Lih-Fen Lue,
Douglas G. Walker,
Periannan Kuppusamy,
Zay L. Zewier,
Ottavio Arancio,
David Stern,
Shirley ShiDu Yan, and
Hao Wu
http://sageke.sciencemag.org/cgi/content/abstract/2004/16/or9
Abstract:
Science 304, 448-452 (2004).
Mitochondrial dysfunction is a hallmark of 
-amyloid (A)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that A-binding alcohol dehydrogenase (ABAD) is a direct molecular link from A to mitochondrial toxicity. A interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of A-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-A interaction and suppresses A-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an A-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-A interaction may be a therapeutic target in AD.
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