Copper-Aβ and cytochrome c: a potential Janus in Alzheimer's disease

Aβ peptides and cytochrome c (Cyt c) co-exist in the mitochondria. The interplay between Aβ and Cyt c is thus, crucial in the context of Alzheimer's disease pathology, where oxidative stress and mitochondrial dysfunction are central features. However, the details of interaction between Cu bound Aβ and Cyt c remain unexplored at a molecular level. Previously it was demonstrated that reduced Cu-Aβ can react with O₂ to result in H₂O₂. This H₂O₂ produced can oxidize neurotransmitters and this process is catalysed by the oxidized Cu-Aβ. Here spectroscopic analyses reveal that reduced Cu-Aβ transfers electron to oxidized Cyt c, which mitigates the production of reactive oxygen species (ROS) by reduced Cu-Aβ species. Thus, Cyt c can exhibit a protective role against ROS generation by Cu-Aβ. On the other hand, the oxidation of reduced Cyt c by H₂O₂ is significantly accelerated in the presence of Cu-Aβ, highlighting the thus far unknown intrinsic Cyt c peroxidase type activity of oxidized Cu-Aβ. Thus, the generation of oxidized Cyt c, catalyzed by Cu-Aβ, raises the possibility of apoptotic death of brain cells which is a common feature associated with AD, thereby revealing the other face of Janus.