TY - JOUR T1 - Extending a systems model of the APP pathway: Separation of β- and γ-secretase sequential cleavage steps of APP JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.244699 SP - jpet.117.244699 AU - Eline T.S. van Maanen AU - Tamara S. van Steeg AU - Maurice Ahsman AU - Maria S. Michener AU - Mary J. Savage AU - Matthew E. Kennedy AU - Huub J. Kleijn AU - Julie A. Stone AU - Meindert Danhof Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/03/21/jpet.117.244699.abstract N2 - 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 APP pathway, describing the Aβ precursor protein (APP) metabolite responses (Aβ40, Aβ42, sAPPα and sAPPβ) to β-secretase 1 (BACE1) inhibition (van Maanen et al., 2016). 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 to BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower AβO levels. Further model refinement and new data may be helpful to fully understand the difference in Aβ dynamics following BACE1 versus GS inhibition. ER -