Authors: Raibatak Das Robert B Nachbar Leah EdelsteinKeshet Jeffrey S Saltzman Matthew C Wiener Ansuman Bagchi James Bailey Daniel Coombs Adam J Simon Richard J Hargreaves Jacquelynn J Cook
Publish Date: 2010/04/22
Volume: 73, Issue: 1, Pages: 230-247
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 γsecretase In this study we examine the temporal dynamics of soluble unaggregated Aβ in the plasma and cerebralspinal fluid CSF of rhesus monkeys treated with different oral doses of a γsecretase inhibitor A dosedependent 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 postdrug 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 timescale of the overshoot These results point to the need for a more detailed investigation of soluble Aβ clearance mechanisms and their interaction with Aβreducing drugs
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