Bulletin of Mathematical Biology

, Volume 73, Issue 1, pp 230–247

Modeling Effect of a γ-Secretase Inhibitor on Amyloid-β Dynamics Reveals Significant Role of an Amyloid Clearance Mechanism

Authors

    • Department of MathematicsUniversity of British Columbia
    • Department of Microbiology and ImmunologyUniversity of British Columbia
  • Robert B. Nachbar
    • Applied Computer Science and Mathematics DepartmentMerck Research Laboratories
  • Leah Edelstein-Keshet
    • Department of MathematicsUniversity of British Columbia
  • Jeffrey S. Saltzman
    • Applied Computer Science and Mathematics DepartmentMerck Research Laboratories
  • Matthew C. Wiener
    • Applied Computer Science and Mathematics DepartmentMerck Research Laboratories
  • Ansuman Bagchi
    • Applied Computer Science and Mathematics DepartmentMerck Research Laboratories
  • James Bailey
    • Department of MathematicsUniversity of British Columbia
  • Daniel Coombs
    • Department of MathematicsUniversity of British Columbia
  • Adam J. Simon
    • Department of Alzheimer’s ResearchMerck Research Laboratories
  • Richard J. Hargreaves
    • Imaging Research DepartmentMerck Research Laboratories
  • Jacquelynn J. Cook
    • Imaging Research DepartmentMerck Research Laboratories
Original Article

DOI: 10.1007/s11538-010-9540-5

Cite this article as:
Das, R., Nachbar, R.B., Edelstein-Keshet, L. et al. Bull. Math. Biol. (2011) 73: 230. doi:10.1007/s11538-010-9540-5

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.

Keywords

γ-secretase inhibitorAmyloid-β clearance
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Supplementary material

11538_2010_9540_MOESM1_ESM.pdf (493 kb)
Supporting Information. (PDF 493 KB)

Copyright information

© Society for Mathematical Biology 2010