Heme-copper-Aβ mediated dopamine oxidation through self-sustaining redox cycling

Alzheimer's disease is characterized by progressive neurodegeneration, with Aβ peptides playing a critical role in disease pathology. Beyond their aggregation into plaques, Aβ peptides can interact with redox-active cofactors such as copper and heme, forming complexes capable of catalyzing ROS generation. While Cu-Aβ is known to oxidise catecholamines like dopamine through redox cycling, the functional implications of ternary heme-Cu-Aβ assemblies remain poorly understood. In this study, we demonstrate that the heme-Cu-Aβ complex catalyzes dopamine oxidation more efficiently than Cu-Aβ alone, driven by a self-sustaining cooperative redox cascade involving Cu-mediated H₂O₂ generation and subsequent heme-mediated peroxidase-like activity in the presence of the endogenously produced H₂O₂. Moreover, kinetic analysis and mutant studies reveal the critical contributions of Arg5 in modulating the redox behavior of the complex. These findings establish the heme-Cu-Aβ complex as a potent catalytic assembly capable of altering dopamine homeostasis under oxidative stress, offering new insights into Aβ-mediated neurotoxicity in Alzheimer's disease.