Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-beta aggregation and toxicity

Cytochrome c (Cyt c), a multifunctional protein with a crucial role in controlling cell fate, has been implicated in the amyloid pathology associated with Alzheimer's disease (AD); however, the interaction between Cyt c and amyloid-beta (A beta) with the consequent impact on the aggregation and toxicity of A beta is not known. Here we report that Cyt c can directly bind to A beta and alter the aggregation and toxicity profiles of A beta in a manner that is dependent on the presence of a peroxide. When combined with hydrogen peroxide (H2O2), Cyt c redirects A beta peptides into less toxic, off-pathway amorphous aggregates, whereas without H2O2, it promotes A beta fibrillization. The mechanisms behind these effects may involve a combination of the complexation between Cyt c and A beta, the oxidation of A beta by Cyt c and H2O2, and the modification of Cyt c by H2O2. Our findings demonstrate a new function of Cyt c as a modulator against A beta amyloidogenesis.