Simultaneous binding of heme and Cu with amyloid β peptides: active site and reactivities

Abstract

Amyloid imbalance and Aβ plaque formation are key histopathological features of Alzheimer's disease (AD). These amyloid plaques observed in post-mortem AD brains have been found to contain increased levels of Cu and deposition of the heme cofactor. The increased Cu concentration and heme co-localization together with other heme related dysfunctions hint towards the likely association of the metal and cofactor in the pathology of the disease. Heme and Cu bind with Aβ separately to form heme–Aβ and Cu–Aβ complexes, respectively. In addition, the metal and cofactor can simultaneously bind with the peptide to generate a physiologically relevant heme–Cu–Aβ complex. In this review, we discuss the active site environment, electronic structure, spectroscopic and electrochemical properties, and some interesting reactivities exhibited by the heme–Cu–Aβ complex with small molecules, such as oxygen (O₂), nitric oxide (NO) and nitrite (NO₂⁻).