Interplay between α-, β-, and γ-Secretases Determines Biphasic Amyloid-β Protein Level in the Presence of a γ-Secretase Inhibitor

Amyloid-beta (A beta) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by beta-secretase, generating C99, and then by gamma-secretase. APP is also cleaved by alpha-secretase. It is hypothesized that reducing the production of A beta in the brain may slow the progression of Alzheimer disease. Therefore, different gamma-secretase inhibitors have been developed to reduce A beta production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in A beta production in different cell lines, in different animal models, and also in humans. A mechanistic understanding of the A beta rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the A beta dynamics in cell lines that exhibit the rise as well as in cell lines that do not. The model includes steps of APP processing through both the so-called amyloidogenic pathway and the so-called non-amyloidogenic pathway. It is shown that the cross-talk between these two pathways accounts for the increase in A beta production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidogenic pathway, redirecting APP to be cleaved by beta-secretase, leading to an additional increase in C99 that overcomes the loss in gamma-secretase activity. With a minor extension, the model also describes plasma A beta profiles observed in humans upon dosing with a gamma-secretase inhibitor. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to humans. This has important implications for the development of drugs targeting A beta production in Alzheimer disease.