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Abstract: Recent reports on amyloid β peptide (Aβ) binding-alcohol dehydrogenase (ABAD) have revealed the link of Aβ with oxidative stress derived from mitochondria in the pathogenesis of Alzheimer''s disease (AD). As a novel function of ABAD, we speculate that ABAD may detoxify aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). To verify this speculation, we transfected cDNA encoding ABAD into cultured cells (HeLa and SH-SY5Y), where ABAD was localized to mitochondria. ABAD-transfectants decreased the levels of externally added 4-HNE in cultured medium as detected by TLC and became resistant against external 4-HNE. Moreover, ABAD suppressed the cytotoxic effects caused by cellular 4-HNE, which were produced through excess reactive oxygen species (ROS) by treatment with an inhibitor of mitochondrial respiration, antimycin A or by adding H2O2. Catabolism of 4-HNE by ABAD was inhibited by Aβ, resulting in the abolishment of the cytoprotective function by ABAD against ROS. These results propose an additional role of ABAD in neural cell death in AD: ABAD detoxifies aldehydes, such as 4-HNE derived from lipid peroxides in healthy brains, and inhibited by Aβ in the development of AD. [Copyright &y& Elsevier]