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J Biol Chem, Vol. 274, Issue 4, 2145-2156, January 22, 1999

Role of ERAB/L-3-Hydroxyacyl-coenzyme A Dehydrogenase Type II Activity in A-induced Cytotoxicity

Shi Du Yan, Yigong Shi^§, Aiping Zhu, Jin Fu, Huaijie Zhu, Yucui Zhu, Lenneen Gibson, Eric Stern, Kate Collison^¶, Futwan Al-Mohanna^¶, Satoshi Ogawa, Alex Roher^**, Steven G. Clarke, and David M. Stern

From the Departments of Pathology, Physiology and Surgery, College of Physicians and Surgeons of Columbia University, New York, New York 10032, the ^¶ King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, the  Department of Anatomy and Neuroscience, Osaka University School of Medicine, Osaka, Japan, the ^§ Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, the ^** Haldeman Laboratory for Alzheimer's Disease Research, Sun Health Research Institute, Sun City, Arizona 85372, and the  Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90024

Endoplasmic reticulum-associated amyloid -peptide (A)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds A, and contributes to A-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a K_m of 68 µM and a V_max of 430 µmol/min/mg. The contribution of ERAB/HADH II enzymatic activity to A-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant -amyloid precursor protein (APP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and APP(V717G) was without effect. We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD⁺ and NAD-dependent oxidation of 17-estradiol. Addition of micromolar levels of synthetic A(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (K_i  1.6 µM), as well as oxidation of 17-estradiol (K_i 3.2 µM) and ()-2-octanol (K_i  2.6 µM). Because micromolar levels of A were required to inhibit ERAB/HADH II activity, whereas A binding to ERAB/HADH II occurred at much lower concentrations (K_m  40-70 nM), the latter more closely simulating A levels within cells, A perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and APP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or APP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected to overexpress Y168G/K172G-altered ERAB and APP(V717G). We conclude that the generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an A-rich environment.

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