Extending a Systems Model of the APP Pathway: Separation of β- and γ-Secretase Sequential Cleavage Steps of APP

The abnormal accumulation of amyloid-β (Aβ) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the amyloid precursor protein (APP) pathway, describing the Aβ APP metabolite responses (Aβ40, Aβ42, sAPPα, and sAPPβ) to β-secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe Aβ dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aβ response to their respective inhibition. Following GS inhibition, a lower Aβ40 formation rate constant was observed, compared with BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower Aβ oligomer levels. Further model refinement and new data may be helpful to fully understand the difference in Aβ dynamics following BACE1 versus GS inhibition.