The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease

Pathogenic changes in gamma-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of gamma-secretase with its substrate. We analyze the saturation of gamma-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of gamma-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic A beta proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-beta CTF-APP substrate and its different A beta products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-beta CTF-APP substrate and beta-secretase path can be more toxic than the C83-alpha CTF-APP substrate and alpha-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-beta CTF-APP substrate to gamma-secretase can be controlled by substrate channeling between the nicastrin and beta-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in gamma-secretase activity and A beta metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between gamma-secretase activity and amyloid metabolism.