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
Eline M T van MaanenMeindert Danhof

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 i...Continue Reading

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Citations

Mar 23, 2018·The Journal of Pharmacology and Experimental Therapeutics·Eline M T van MaanenMeindert Danhof
Aug 12, 2017·Journal of Alzheimer's Disease : JAD·Stephanie VillarrealMatthew E Kennedy
Sep 20, 2019·CPT: Pharmacometrics & Systems Pharmacology·Erica L BradshawJason R Chan
May 4, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Kumpal MadrasiFei Hua

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