An important means of determining how amyloid-beta peptide (Abeta) affects cells is to identify specific macromolecular targets and assess how Abeta interaction with such targets impacts on cellular functions. On the one hand, cell surface receptors interacting with extracellular Abeta 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 Abeta in cell stress associated with amyloidosis. Thus, specific intracellular targets of Abeta might also be of interest. Our review evaluates the potential significance of Abeta interaction with a mitochondrial enzyme termed Abeta-binding alcohol dehydrogenase (ABAD), a member of the short-chain dehydrogenase-reductase family concentrated in mitochondria of neurones. Binding of Abeta 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 Abeta-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 Abeta-rich environment.