Bulletin of Mathematical Biology

, Volume 73, Issue 1, pp 230–247 | Cite as

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

  • Raibatak Das
  • Robert B. Nachbar
  • Leah Edelstein-Keshet
  • Jeffrey S. Saltzman
  • Matthew C. Wiener
  • Ansuman Bagchi
  • James Bailey
  • Daniel Coombs
  • Adam J. Simon
  • Richard J. Hargreaves
  • Jacquelynn J. Cook
Original Article

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 inhibitor Amyloid-β clearance 

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Supplementary material

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Copyright information

© Society for Mathematical Biology 2010

Authors and Affiliations

  • Raibatak Das
    • 1
    • 2
  • Robert B. Nachbar
    • 3
  • Leah Edelstein-Keshet
    • 1
  • Jeffrey S. Saltzman
    • 3
  • Matthew C. Wiener
    • 3
  • Ansuman Bagchi
    • 3
  • James Bailey
    • 1
  • Daniel Coombs
    • 1
  • Adam J. Simon
    • 4
  • Richard J. Hargreaves
    • 5
  • Jacquelynn J. Cook
    • 5
  1. 1.Department of MathematicsUniversity of British ColumbiaVancouverCanada
  2. 2.Department of Microbiology and ImmunologyUniversity of British ColumbiaVancouverCanada
  3. 3.Applied Computer Science and Mathematics DepartmentMerck Research LaboratoriesRahwayUSA
  4. 4.Department of Alzheimer’s ResearchMerck Research LaboratoriesWest PointUSA
  5. 5.Imaging Research DepartmentMerck Research LaboratoriesWest PointUSA

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