Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2

Abstract

β-Amyloid (Aβ) 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. Aβ·Cu complexes generate neurotoxic H2O2 from O2 through Cu2+ reduction, but the reaction mechanism has been unclear. We now report that Aβ1-42, when binding up to 2 eq of Cu2+, generates the H2O2 catalytically by recruiting biological reducing agents as substrates under conditions where the Cu2+ 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, Km = 8.9 μM). The activity was inhibited by anti-A..