ABAD directly links A[beta] to mitochondrial toxicity in Alzheimer's disease

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