Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β 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-β (Aβ) with the consequent impact on the aggregation and toxicity of Aβ is not known. Here we report that Cyt c can directly bind to Aβ and alter the aggregation and toxicity profiles of Aβ in a manner that is dependent on the presence of a peroxide. When combined with hydrogen peroxide (H 2 O 2 ), Cyt c redirects Aβ peptides into less toxic, off-pathway amorphous aggregates, whereas without H 2 O 2 , it promotes Aβ fibrillization. The mechanisms behind these effects may involve a combination of the complexation between Cyt c and Aβ, the oxidation of Aβ by Cyt c and H 2 O 2 , and the modification of Cyt c by H 2 O 2 . Our findings demonstrate a new function of Cyt c as a modulator against Aβ amyloidogenesis.