Active Site Environment and Reactivity of Copper‐Aβ in Membrane Mimetic SDS Micellar Environment

Abstract

AbstractAlzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid β (Aβ) peptide in extracellular deposits generated upon proteolysis of Amyloid Precursor Protein (APP). While copper (Cu(II)) binds to Aβ in soluble oligomeric and aggregated forms, its interaction with membrane‐bound Aβ remains elusive. Investigating these interactions is crucial for understanding AD pathogenesis. Here, utilizing SDS micelles as a simplified membrane mimic, we focus on elucidating the interplay between membrane‐anchored Aβ and copper, given their pivotal roles in AD. We employed spectroscopic techniques including UV, CD, and EPR to characterize the active site of Cu‐Aβ complexes. Our findings demonstrate that copper interacts with Aβ peptides in membrane‐mimicking micellar environments similarly to aqueous buffer solutions. Cu‐Aβ complexes in this medium also induce higher hydrogen peroxide (H2O2) production, potentially contributing to AD‐related oxidative stress. Moreover, we observe an increased oxidation rate of neurotransmitter such as dopamine by Cu‐Aβ complexes. These results enhance our understanding of Cu‐Aβ interactions in AD pathology and offer insights into potential therapeutic interventions targeting this interaction.