Computational models explain how copper binding to amyloid-β peptide oligomers enhances oxidative pathways.

Amyloid-β (Aβ) peptides are intrinsically disordered peptides and their aggregation is the major hallmark of Alzheimer's disease (AD) development. The interactions between copper ions and Aβ peptides create catalysts that activate the production of reactive oxygen species in the synaptic region, a reactivity that is strongly related to AD onset. Recent experimental work [Gu et al., Sci. Rep., 2018, 8(1), 16190] confirmed that the oxidative reactivity of Cu-Aβ catalyzes the formation of Tyr-Tyr crosslinks in peptide dimers. This work provides a structural basis to these observations, describing structures of Cu-Aβ dimers that enhance the propagation of the oxidative pathways activated around the Cu center. Among these, the formation of Tyr-Tyr crosslinks becomes more likely when previous crosslinks involve Cu forming bridges between different peptides. Peptides are, therefore, easily assembled into dimers and tetramers, the latter being dimers of dimers. The size of such dimers and tetramers fits with ion mobility mass spectrometry results [Sitkiewicz et al., J. Mol. Biol., 2014, 426(15), 2871].