title: Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool.
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.
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Eline M T
authors.initials: EM
authors.lastname: van Maanen
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: van Steeg
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Huub Jan
authors.initials: HJ
authors.lastname: Kleijn
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.).
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stone
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics, Leiden, The Netherlands (E.M.T.v.M., T.J.v.S.); Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (E.M.T.v.M., M.D.); and Merck Research Laboratories, Whitehouse Station, New Jersey (M.S.M., M.J.S., M.E.K., H.J.K., J.A.S.) m.danhof@lacdr.leidenuniv.nl.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000465:Algorithms; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D001923:Brain Chemistry / Q000187:drug effects; D002946:Cisterna Magna; D004305:Dose-Response Relationship, Drug; D007267:Injections; D008253:Macaca mulatta; D008297:Male; D015233:Models, Statistical; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases