Fernando Ortega
Pharmacometrics Research Group. School of Pharmacy. The University of Manchester. UK
Objectives: To develop a mathematical model to describe Amyloid- β (Aβ) dynamics and to identify and analyze the factors in the amyloid processing pathway that contribute to the rise in Aβ levels at low inhibitor concentrations. The second aim is to examine whether the Aβ formation model can quantitatively describe in vitro dose response experiments in different cell lines.
Methods: Amyloid metabolism data was compiled from the literature [e.g. 1,2] and used to build a minimal kinetic model of Aβ production, in particular around APP degradation leading to Aβ formation. We propose that the processing steps obey Michaelis-Menten. The inhibitors dose response curves were fitted to the in vitro and in vivo data for model parameter estimation.
Results: Here, a minimal mathematical model has been developed that quantitatively describes the Aβ dynamics in cell lines which exhibit the rise of Aβ as well as in cell lines which do not. The model includes steps of APP processing through both the so-called amyloidagenic and non-amyloidagenic pathway. It is shown that the cross-talk between these two pathways account for the increase in Aβ production in response to inhibitor. With a minor extension, the model also describes plasma Aβ profiles observed in man upon dosing with a GSI [3].
Conclusions: The mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to man. This has important implications for the development of drugs targeting Aβ production in AD.
References:
[1] Burton CR, et al (2008) The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression . J Biol Chem 283: 22992-23003.
[2] Lanz TA, et al (2006) Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319: 924-933.
[3] Ortega F, et al (2013) Interplay between α, β and γ-secretases determines biphasic Aβ level in the presence of a γ-secretases inhibitor. J Biol Chem 288: 785-792.
Reference: PAGE 24 (2015) Abstr 3573 [www.page-meeting.org/?abstract=3573]
Poster: Drug/Disease modeling - CNS