Interaction of NO with Cu and Heme-Bound Aß Peptides Associated with Alzheimer's Disease.

Reduced Cu and heme has been invoked to be involved in Alzheimer's disease (AD). Recently the Aß peptides have been demonstrated to bind heme and Cu simultaneously, and this complex produces significandy more toxic partially reduced oxygen species (PROS) than the Cu or heme-bound Aß peptides. Here a combination of absorption, EPR, and resonance Raman spectroscopy along with kinetic assays are used to investigate the interaction of nitric oxide (NO) with the physiologically relevant form of Cu and heme-bound Aß peptides, since a down-regulation of nitric oxide synthase activity is observed in patients suffering from AD. The data indicate that NO oxidizes the Cu(l) sites, making them less toxic toward PROS generation and releases heme from the Aß peptides ameliorating the effects of heme binding to Aß peptides associated with AD. This process involves a tyrosine-mediated electron transfer between the Cu and heme sites. These results provide a mechanistic pathway for the possible protective role of NO in AD. [ABSTRACT FROM AUTHOR]