Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-ß 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-ß (Aß) with the consequent impact on the aggregation and toxicity of Aß is not known. Here we report that Cyt c can directly bind to Aß and alter the aggregation and toxicity profiles of Aß in a manner that is dependent on the presence of a peroxide. When combined with hydrogen peroxide (H2O2), Cyt c redirects Aß peptides into less toxic, off-pathway amorphous aggregates, whereas without H2O2, it promotes Aß fibrillization. The mechanisms behind these effects may involve a combination of the complexation between Cyt c and Aß, the oxidation of Aß 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 Aß amyloidogenesis.