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

Alzheimer'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.