Mitochondrial dysfunction and Alzheimer's disease:: role of amyloid-β peptide alcohol dehydrogenase (ABAD)

An important means of determining how amyloid-beta peptide (A beta) affects cells is to identify specific macromolecular targets and assess how A beta interaction with such targets impacts on cellular functions. On the one hand, cell surface receptors interacting with extracellular A beta have been identified, and their engagement by amyloid peptide can trigger intracellular signaling cascades. Recent evidence has indicated a potentially significant role for deposition of intracellular A beta in cell stress associated with amyloidosis. Thus, specific intracellular targets of A beta might also be of interest. Our review evaluates the potential significance of A beta interaction with a mitochondrial enzyme termed A beta-binding alcohol dehydrogenase (ABAD), a member of the short-chain dehydrogenase-reductase family concentrated in mitochondria of neurones. Binding of A beta to ABAD distorts the enzyme's structure, rendering it inactive with respect to its metabolic properties, and promotes mitochondrial generation of free radicals. Double transgenic mice in which increased levels of ABAD are expressed in an A beta-rich environment, the latter provided by a mutant amyloid precursor protein transgene, demonstrate accelerated decline in spatial learning/memory and pathologic changes. These data suggest that mitochondria ABAD, ordinarily a contributor to metabolic homeostasis, has the capacity to become a pathogenic factor in an A beta-rich environment.