Das2010 - Effect of a gamma-secretase inhibitor on Amyloid-beta dynamics

Das2010 - Effect of a gamma-secretase
inhibitor on Amyloid-beta dynamics

This model is described in the article:

Modeling effect of a
?-secretase inhibitor on amyloid-? dynamics reveals significant
role of an amyloid clearance mechanism.

Das R, Nachbar RB, Edelstein-Keshet
L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon
AJ, Hargreaves RJ, Cook JJ.
Bull. Math. Biol. 2011 Jan; 73(1):
230-247
Abstract:

Aggregation of the small peptide amyloid beta (A?) into
oligomers and fibrils in the brain is believed to be a
precursor to Alzheimer's disease. A? is produced via multiple
proteolytic cleavages of amyloid precursor protein (APP),
mediated by the enzymes ?- and ?-secretase. In this study, we
examine the temporal dynamics of soluble (unaggregated) A? in
the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys
treated with different oral doses of a ?-secretase inhibitor. A
dose-dependent reduction of A? concentration was observed
within hours of drug ingestion, for all doses tested. A?
concentration in the CSF returned to its predrug level over the
monitoring period. In contrast, A? 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 A? dynamics that could fit the data. Our analysis
suggests that the overshoot arises from the attenuation of an
A? clearance mechanism, possibly due to the inhibitor. Our
model predicts that the efficacy of A? 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 A? clearance mechanisms and their interaction with
A?-reducing drugs.

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