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

• Published in: Science (American Association for the Advancement of Science) 2004-04, Vol.304 (5669), p.448-452
• Main 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
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biological and medical sciences; Causes of; Cerebral cortex; Chemical properties; Crystal structure; Crystals; Cytochromes; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Medical sciences; Mitochondria; Mitochondrial diseases; Neurology; Neurons; Oxidative stress; Reactive oxygen species; Research universities; Transgenic animals
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1091230

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.