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Science 16 April 2004:
Vol. 304. no. 5669, pp. 448 - 452
DOI: 10.1126/science.1091230
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Reports

ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease

Joyce W. Lustbader,1* Maurizio Cirilli,3*{dagger} Chang Lin,2*{ddagger} Hong Wei Xu,2,4 Kazuhiro Takuma,2§ Ning Wang,2{ddagger} Casper Caspersen,2 Xi Chen,5 Susan Pollak,1 Michael Chaney,2 Fabrizio Trinchese,6 Shumin Liu,6 Frank Gunn-Moore,7 Lih-Fen Lue,8 Douglas G. Walker,8 Periannan Kuppusamy,9 Zay L. Zewier,9 Ottavio Arancio,6 David Stern,10 Shirley ShiDu Yan,2|| Hao Wu3||

Mitochondrial dysfunction is a hallmark of ß-amyloid (Aß)–induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aß-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aß to mitochondrial toxicity. Aß interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aß-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aß interaction and suppresses Aß-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aß-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aß interaction may be a therapeutic target in AD.

1 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.
2 Departments of Pathology and Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
3 Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
4 Department of Immunology, Harbin Medical University, Harbin 150086, China.
5 Department of Neurology, New York University, New York, NY 10003, USA.
6 Dementia Research Center, Nathan Kline Institute and Department of Psychiatry, Physiology and Neuroscience, New York University, New York, NY 10016, USA.
7 School of Biology, Bute Medical Building, University of St. Andrews, St. Andrews KY16 9TS, Scotland, UK.
8 Sun Health Research Institute, Sun City, AZ 85351, USA.
9 David Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
10 Dean's Office, Medical College of Georgia, Augusta, GA 30912, USA.



* These authors contributed equally to the work.

{dagger} Present address: Institute of Neurobiology and Molecular Medicine–Italian National Council of Research, Via del Fosso del Cavaliere, 100, 00133 Rome, Italy.

{ddagger} Present address: Departments of Otolaryngology and Neurology, First Affiliated Hospital, Fujian Medical University, Fujian 350005, China.

§ Present address: Department of Analytical Chemistry, Faculty of Pharmaceutical Science, Kobe Gakuin University, Kobe 651–2180, Japan.

|| These authors contributed equally to the work.

To whom correspondence should be addressed. E-mail: haowu{at}med.cornell.edu (H.W.); sdy1{at}columbia.edu (S.S.Y.)

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