ABAD Directly Links Aß 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, Hao Wu- Multidisciplinary
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.