查看文章

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 H₂O₂catalytically 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 (V _maxfor dopamine=34.5 nm/min, K _m = 8.9 μm). The activity was inhibited by anti-Aβ antibodies, Cu²⁺ chelators, and Zn²⁺. Toxicity of Aβ in neuronal culture was consistent with catalytic H₂O₂ production. Aβ was not toxic in cell cultures in the absence of Cu²⁺, and dopamine (5 μm) markedly …