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Large and small aggregates of Aβ peptides, resembling the morphology and dimensions of fibrillar and oligomeric forms of Aβ respectively, relevant to Alzheimer's disease, are stabilized on electrodes using selfassembly. Both of these forms were found to bind redox active Cu and heme, resulting in active sites having distinctive biophysical properties. The reduced metal bound Aβ active sites of both the oligomeric and fibrillar forms of Aβ produce detrimental partially reduced oxygen species (PROS). While the larger aggregates of heme-Aβ produce more PROS in situ, the smaller aggregates of Cu-Aβ produce more PROS. 8-Hydroxy quinoline and methylene blue are inhibitors of Cu and heme bound Aβ respectively, and are shown to efficiently reduce PROS formation in the oligomeric forms. However, these inhibitors are ineffective in reducing the toxicities of the Cu and heme bound Aβ peptides in the fibrils, making them significantly more lethal than the smaller Aβ aggregates. [ABSTRACT FROM AUTHOR]

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]

Recent reports show that there is a large increase in heme in the temporal brain of Alzheimer's disease (AD) patients, as heme, biosynthesized in brain cells, binds to amyloid β (Aβ), forming heme-Aβ complexes. This leads to the development of symptoms that are characteristic pathological features of AD, e.g., abnormal iron homeostasis, decay of iron regulatory proteins, dysfunction in mitochondrial complex IV, oxidative stress, etc. However, the active site resulting from heme binding to Aβ is not well characterized. For example, the coordinating residue, relevant second-sphere residues, and spin state of the Fe center are not known. In this study we have used wild-type and mutated Aβ peptides and investigated their interaction with naturally occurring heme. Our results show that, out of several possible binding sites, His13 and His14 residues can both bind heme under physiological conditions, resulting in an axial high-spin active site with a trans axial water-derived ligand. Peroxidase assays of these heme-peptide complexes along with pH perturbations indicate that Arg5 is a key second-sphere residue that H-bonds to the trans axial ligand and is responsible for the peroxidase activity of the heme-Aβ complexes. The His13 and Arg5 residues identified in this study are both absent in rodents, which do not show AD, implicating the significance of these residues as well as heme in the pathology of AD. [ABSTRACT FROM AUTHOR]