Self-assembly of stable oligomeric and fibrillar aggregates of Aβ peptides relevant to Alzheimer's disease: morphology dependent Cu/heme toxicity and inhibition of PROS generation

Large and small aggregates of A beta peptides, resembling the morphology and dimensions of fibrillar and oligomeric forms of A beta respectively, relevant to Alzheimer's disease, are stabilized on electrodes using self-assembly. 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 A beta active sites of both the oligomeric and fibrillar forms of A beta produce detrimental partially reduced oxygen species (PROS). While the larger aggregates of heme-A beta produce more PROS in situ, the smaller aggregates of Cu-A beta produce more PROS. 8-Hydroxy quinoline and methylene blue are inhibitors of Cu and heme bound A beta 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 A beta peptides in the fibrils, making them significantly more lethal than the smaller A beta aggregates.