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

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

This model is described in the article:

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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Format
SBML (L2V4)
Related Publication
  • Modeling effect of a γ-secretase inhibitor on amyloid-β 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
  • Bulletin of mathematical biology , 1/ 2011 , Volume 73 , pages: 230-247
  • Department of Mathematics, University of British Columbia, 1984 Mathematics Road, Vancouver, BC V6T 1Z2, Canada. dodo@math.ubc.ca
  • 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.
Contributors
Audald Lloret i Villas

Metadata information

is
BioModels Database MODEL1409230000
BioModels Database BIOMD0000000551
isDescribedBy
PubMed 20411345
hasTaxon
Taxonomy Macaca mulatta
isVersionOf
Gene Ontology amyloid-beta clearance
hasProperty
Human Disease Ontology Alzheimer's disease
Curation status
Curated
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Sep 23, 2014 1:18:51 PM
  • Last Modified: Apr 8, 2016 6:42:21 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 8, 2016 6:42:21 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Das2010 - Effect of a gamma-secretase inhibitor on Amyloid-beta dynamics
  • Version: 1 public model Download this version
    • Submitted on: Sep 23, 2014 1:18:51 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Das2010 - Effect of a gamma-secretase inhibitor on Amyloid-beta dynamics
Curator's comment:
(added: 30 Sep 2014, 15:55:58, updated: 30 Sep 2014, 15:55:58)
Notes: Figure 4 of the reference publication has been reproduced here In this model some parameters are missing. Optimization is done in order to fit the figure. See values: - Deltap = 0.55 - K1 = 1.13 - r = 0.43 Dynamics of A? in CSF and plasma with a dose of 120 mpk of gamma-secretase inhibitor are plotted during 72 hours. The simulation was done using Copasi v4.12 (Build 81) and the plos were generated using Gnuplot. The Copasi file of the model wih simulation setings can be downloaded from the below link: