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Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool.

Authors :
van Maanen EM
van Steeg TJ
Michener MS
Savage MJ
Kennedy ME
Kleijn HJ
Stone JA
Danhof M
Source :
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2016 Apr; Vol. 357 (1), pp. 205-16. Date of Electronic Publication: 2016 Jan 29.
Publication Year :
2016

Abstract

The deposition of amyloid-β (Aβ) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the β-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aβ42, Aβ40, soluble β-amyloid precursor protein (sAPP) α, and sAPPβ in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites. Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPα and dose-dependent decreases of sAPPβ and Aβ were observed. Maximal inhibition of BACE1 was close to 100% and the IC50 value was 0.0256 μM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Aβ40 and Aβ42 was observed, with the Aβ40 response being larger than the Aβ42 response. This enabled the identification of an Aβ42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Aβ responses resulting from BACE1 inhibition are partially compensated by dissociation of Aβ oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.<br /> (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Details

Language :
English
ISSN :
1521-0103
Volume :
357
Issue :
1
Database :
MEDLINE
Journal :
The Journal of pharmacology and experimental therapeutics
Publication Type :
Academic Journal
Accession number :
26826190
Full Text :
https://doi.org/10.1124/jpet.115.230565