Opazo, CarlosHuang, XudongCherny, Robert A.Moir, Robert D.Roher, Alex E.White, Anthony R.Cappai, RobertoMasters, Colin L.Tanzi, Rudolph E.Inestrosa, Nibaldo C.Bush, Ashley I.2021-11-232002-08-20Opazo, Carlos, Xudong Huang, Robert A. Cherny, Robert D. Moir, Alex E. Roher, Anthony R. White, Roberto Cappai et al. "Metalloenzyme-like Activity of Alzheimer's Disease β-Amyloid." Journal of Biological Chemistry 277, no. 43 (2002): 40302-40308. DOI: 10.1074/jbc.m2064282000021-92581083-351Xhttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37370312Beta-Amyloid (Abeta) 1–42, implicated in the pathogenesis of Alzheimer’s disease, forms an oligomeric complex that binds copper at a CuZn superoxide dismutase-like binding site. Abeta.Cu complexes generate neurotoxic H2O2 from O2 through Cu(2+) reduction, but the reaction mechanism has been unclear. We now report that Abeta1– 42, when binding up to 2 eq of Cu(2+), generates the H2O2 catalytically by recruiting biological reducing agents as substrates under conditions where the Cu(2+) or reducing agents will not form H2O2 themselves. Cholesterol is an important substrate for this activity, as are vitamin C, L-DOPA, and dopamine (Vmax for dopamine = 34.5 nM/min, K(m) = 8.9 microM). The activity was inhibited by anti-Abeta antibodies, Cu(2+) chelators, and Zn(2+). Toxicity of Abeta in neuronal culture was consistent with catalytic H2O2 production. Abeta was not toxic in cell cultures in the absence of Cu(2+), and dopamine (5 microM) markedly exaggerated the neurotoxicity of 200 nM Abeta1– 42.Cu. Therefore, microregional catalytic H2O2 production, combined with the exhaustion of reduc- ing agents, may mediate the neurotoxicity of Abeta in Alzheimer’s disease, and inhibitors of this novel activity may be of therapeutic value.en-USCell BiologyMolecular BiologyBiochemistryJournal Article2021-11-2310.1074/jbc.m206428200