Amyloid- -peptide reduces copper(II) to copper(I) independent of its aggregation state

Alzheimer’s disease (AD) is characterized by the deposition of amyloid b-peptide (A ) and neuronal degeneration in brain regions involved in learning and memory. One of the leading etiologic hypotheses regarding AD is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Recent evidence suggests that metals concentrated in amyloid deposits may contribute to the oxidative insults observed in AD-affected brains. We hypothesized that A peptide in the presence of copper enhances its neurotoxicity generating free radicals via copper reduction. In the present study, we have examined the effect of the aggregation state of amyloid- -peptide on copper reduction. In independent experiments we measured the copper-reducing ability of soluble and fibrillar A 1-40 forms by bathocuproine assays. As it was previously observed for the amyloid precursor protein (APP), the A peptide showed copper-reducing ability. The capacity of A to reduce copper was independent of the aggregation state. Finally, the A peptide derived from the human sequence has a greater effect than the A peptide derived from the rat sequence, suggesting that histidine 13 may play a role in copper reduction. In agreement with this possibility, the A peptide reduces less copper in the presence of exogenous histidine