Original Article

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

  • Raibatak DasAffiliated withDepartment of Mathematics, University of British ColumbiaDepartment of Microbiology and Immunology, University of British Columbia Email author 
  • , Robert B. NachbarAffiliated withApplied Computer Science and Mathematics Department, Merck Research Laboratories
  • , Leah Edelstein-KeshetAffiliated withDepartment of Mathematics, University of British Columbia
  • , Jeffrey S. SaltzmanAffiliated withApplied Computer Science and Mathematics Department, Merck Research Laboratories
  • , Matthew C. WienerAffiliated withApplied Computer Science and Mathematics Department, Merck Research Laboratories
  • , Ansuman BagchiAffiliated withApplied Computer Science and Mathematics Department, Merck Research Laboratories
  • , James BaileyAffiliated withDepartment of Mathematics, University of British Columbia
  • , Daniel CoombsAffiliated withDepartment of Mathematics, University of British Columbia
  • , Adam J. SimonAffiliated withDepartment of Alzheimer’s Research, Merck Research Laboratories
    • , Richard J. HargreavesAffiliated withImaging Research Department, Merck Research Laboratories
    • , Jacquelynn J. CookAffiliated withImaging Research Department, Merck Research Laboratories

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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