title: Modeling effect of a γ-secretase inhibitor on amyloid-β dynamics reveals significant role of an amyloid clearance mechanism.
abstract: Aggregation of the small peptide amyloid beta (Aβ) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer's disease. Aβ is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes β- and γ-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) Aβ in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a γ-secretase inhibitor. A dose-dependent reduction of Aβ concentration was observed within hours of drug ingestion, for all doses tested. Aβ concentration in the CSF returned to its predrug level over the monitoring period. In contrast, Aβ concentration in the plasma exhibited an unexpected overshoot to as high as 200% of the predrug concentration, and this overshoot persisted as late as 72 hours post-drug ingestion. To account for these observations, we proposed and analyzed a minimal physiological model for Aβ dynamics that could fit the data. Our analysis suggests that the overshoot arises from the attenuation of an Aβ clearance mechanism, possibly due to the inhibitor. Our model predicts that the efficacy of Aβ clearance recovers to its basal (pretreatment) value with a characteristic time of >48 hours, matching the time-scale of the overshoot. These results point to the need for a more detailed investigation of soluble Aβ clearance mechanisms and their interaction with Aβ-reducing drugs.
authors.affiliation: Department of Mathematics, University of British Columbia, 1984 Mathematics Road, Vancouver, BC V6T 1Z2, Canada. dodo@math.ubc.ca
authors.forename: Raibatak
authors.initials: R
authors.lastname: Das
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nachbar
authors.forename: Leah
authors.initials: L
authors.lastname: Edelstein-Keshet
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Saltzman
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wiener
authors.forename: Ansuman
authors.initials: A
authors.lastname: Bagchi
authors.forename: James
authors.initials: J
authors.lastname: Bailey
authors.forename: Daniel
authors.initials: D
authors.lastname: Coombs
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008253:Macaca mulatta; D055641:Mathematical Concepts; D023421:Models, Animal; D008954:Models, Biological; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases