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 (A β ) 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 A β APP metabolite responses (A β 40, A β 42, sAPP α , and sAPP β ) to β -secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe A β 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 A β response to their respective inhibition. Following GS inhibition, a lower A β 40 formation rate constant was observed, compared with BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower A β oligomer levels. Further model refinement and new data may be helpful to fully understand the difference in A β dynamics following BACE1 versus GS inhibition.