Amyloid beta-peptide-binding alcohol dehydrogenase (ABAD) is a member of the family of short chain dehydrogenase/reductases whose distinctive properties include the capacity to bind amyloid beta-peptide and enzymatic activity toward a broad array of substrates including n-isopropanol and beta-estradiol. In view of the wide substrate specificity of ABAD and its high activity on l-beta-hydroxyacyl-CoA derivatives, we asked whether it might also catalyze the oxidation of the ketone body d-3-hydroxybutyrate. This was indeed the case, and oxidation proceeded with K(m) of approximately 4.5 mm and V(max) of approximately 4 nmol/min/mg protein. When placed in medium with d-beta-hydroxybutyrate as the principal energy substrate, COS cells stably transfected to overexpress wild-type ABAD (COS/wtABAD) better maintained 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, cellular energy charge, and morphologic phenotype compared with COS/vector cells. Using a severe model of metabolic perturbation, transgenic mice with targeted neuronal expression of ABAD subjected to transient middle cerebral artery occlusion showed strokes of smaller volume and lower neurologic deficit scores in parallel with increased brain ATP and decreased lactate, compared with nontransgenic controls. These data suggest that ABAD contributes to the protective response to metabolic stress, especially in the setting of ischemia.