A systems pharmacology approach unravels the dynamics of the APP pathway and unfolds Aß oligomer modulation
Eline M.T. van Maanen
(1) LACDR, Leiden University, The Netherlands; (2) LAP&P, Leiden, The Netherlands
Objectives: In Alzheimer’s Disease, amyloid-β (Aβ) levels are increased early forming toxic soluble Aβ oligomers (AβO) and plaques. Drug effects on the individual attributes of the amyloid precursor protein (APP) pathway are difficult to predict, because it involves a biological network. The objectives were: (1) To further develop an existing APP systems pharmacology model [3], describing drug effects on individual attributes and their interrelationships; (2) To elucidate the relationship between the AβOs and monomeric Aβ.
Methods: In a 4-way crossover study in monkeys [1] the effects of a BACE1 (MBi-5; 30, 125 mg/kg) and a GS (L675; 240 mg/kg) inhibitor on the CSF concentrations of sAPPβ, Aβ40, Aβ42, Aβ38, AβO and sAPPα were determined. An existing APP systems model [3], was extended in two steps: (1) Aβ38 and AβO response were included and the relationship between monomeric Aβ species and AβO was investigated. (2) The model was extended to GS inhibitor response data and the resilience of the APP pathway was investigated.
Results: The APP systems model quantified the effects on all six biomarkers adequately. The BACE1 effect was described by inhibition of formation of C99 and sAPPβ out of APP. The GS effect was described by inhibition of Aβ formation out of C99. The increase in C99 after GS inhibition stimulated α-secretase processing of APP indicating a homeostatic feedback loop. The ratio Aβ42:Aβ40:Aβ38 following BACE1 vs. GS inhibition was found different and was explained by stepwise successive cleavage of C99 by GS, where part of Aβ38 is formed from Aβ42. The APP systems model integrated information from an AβO assay [2] with the PK and APP metabolites concentration measurements in response to both treatments. Interestingly, it was found that: (i) Aβ oligomerization was a higher order process; (ii) Both inhibition of BACE1 and GS resulted in similar reduction profiles for AβOs; (iii) Aβ42 was the only contributor to the oligomer pool.
Conclusions: BACE1 and GS inhibition reduce the putatively neurotoxic oligomer pool. A large change from baseline for AβO compared to monomeric Aβ species is obtained following BACE1 or GS inhibition because oligomerization is a higher order process, The model suggested that GS inhibition enhances the non-amyloidogenic processing of APP by homeostatic feedback via C99. The APP systems pharmacology model can bring us closer to optimizing the therapeutic intervention to reduce AβO burden.
References:
[1] Gilberto DB, Zeoli AH, Szczerba PJ, Gehret JR, Holahan MA, Sitko GR, et al. An alternative method of chronic cerebrospinal fluid collection via the cisterna magna in conscious rhesus monkeys. Contemp Top Lab Anim Sci. 2003;42(4):53–9.
[2] Savage, M. J., Kalinina, J., Wolfe, A., Tugusheva, K., Korn, R., Cash-Mason, T., … McCampbell, A. (2014). A sensitive Aβ oligomer assay discriminates Alzheimer’s and aged control cerebrospinal fluid. The Journal of Neuroscience, 34(8), 2884–97.
[3] van Maanen, E. M. T., van Steeg, T. J., Michener, M. S., Savage, M. J., Kennedy, M. E., Kleijn, H. J., … Danhof, M. (2016). Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool. The Journal of Pharmacology and Experimental Therapeutics, 357(1), 205–16.