Ortega2013 - Interplay between secretases determines biphasic amyloid-beta level

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Ortega2013 - Interplay between secretases determines biphasic amyloid-beta level

This model is described in the article:

Ortega F, Stott J, Visser SA, Bendtsen C.
J. Biol. Chem. 2013 Jan; 288(2): 785-792

Abstract:

Amyloid-? (A?) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by ?-secretase, generating C99, and then by ?-secretase. APP is also cleaved by ?-secretase. It is hypothesized that reducing the production of A? in the brain may slow the progression of Alzheimer disease. Therefore, different ?-secretase inhibitors have been developed to reduce A? production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in A? production in different cell lines, in different animal models, and also in humans. A mechanistic understanding of the A? rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the A? dynamics in cell lines that exhibit the rise as well as in cell lines that do not. The model includes steps of APP processing through both the so-called amyloidogenic pathway and the so-called non-amyloidogenic pathway. It is shown that the cross-talk between these two pathways accounts for the increase in A? production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidogenic pathway, redirecting APP to be cleaved by ?-secretase, leading to an additional increase in C99 that overcomes the loss in ?-secretase activity. With a minor extension, the model also describes plasma A? profiles observed in humans upon dosing with a ?-secretase inhibitor. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to humans. This has important implications for the development of drugs targeting A? production in Alzheimer disease.

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Format
SBML (L2V4)
Related Publication
  • Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.
  • Ortega F, Stott J, Visser SA, Bendtsen C
  • The Journal of biological chemistry , 1/ 2013 , Volume 288 , pages: 785-792
  • Computational Biology, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
  • Amyloid-β (Aβ) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by β-secretase, generating C99, and then by γ-secretase. APP is also cleaved by α-secretase. It is hypothesized that reducing the production of Aβ in the brain may slow the progression of Alzheimer disease. Therefore, different γ-secretase inhibitors have been developed to reduce Aβ production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in Aβ production in different cell lines, in different animal models, and also in humans. A mechanistic understanding of the Aβ rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the Aβ dynamics in cell lines that exhibit the rise as well as in cell lines that do not. The model includes steps of APP processing through both the so-called amyloidogenic pathway and the so-called non-amyloidogenic pathway. It is shown that the cross-talk between these two pathways accounts for the increase in Aβ production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidogenic pathway, redirecting APP to be cleaved by β-secretase, leading to an additional increase in C99 that overcomes the loss in γ-secretase activity. With a minor extension, the model also describes plasma Aβ profiles observed in humans upon dosing with a γ-secretase inhibitor. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to humans. This has important implications for the development of drugs targeting Aβ production in Alzheimer disease.
Contributors
Audald Lloret i Villas

Metadata information

is
BioModels Database MODEL1409240000
BioModels Database BIOMD0000000556
isDescribedBy
PubMed 23152503
hasTaxon
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology Alzheimer's disease
Curation status
Curated
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: 24-Sep-2014 10:25:01
  • Last Modified: 08-Apr-2016 18:43:10
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-Apr-2016 18:43:10
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Ortega2013 - Interplay between secretases determines biphasic amyloid-beta level
  • Version: 1 public model Download this version
    • Submitted on: 24-Sep-2014 10:25:01
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Ortega2013 - Amyloid-beta protein level in the presence of a gamma-secretase inhibitor
Curator's comment:
(added: 19 Nov 2014, 16:03:20, updated: 19 Nov 2014, 16:03:20)
Quantitative modelling of the A? response across a range of inhibitor concentrations in two cell types (see below) from Figure 3 has been reproduced here. Percent of A? concentration after 16 hours along a range of inhibitor concentration (log scale -2 to 4) respect A? concentration when no drug treatment is applied. Legend: APPwt = cell type within wild type APP APPswe = cell type within Swedish mutation APP DAPT = gamma-secretase inhibitor drug N-[N-(3,5-Difluorophenacetyl)-alanyl]-S-phenylglycine t-butyl ester Reactions for different conditions are found in Table 1 and 2 of the paper. Secretase and inhibitor parameter values are found in Table S1a and S1b of the Supplementary section. The simulation was done using Copasi v4.12 (Build 81) and the plots were generated using Gnuplot. Figure 3 is simulated by dividing the drug condition output by the no-drug condition output. The models with simulation settings can be downloaded from the below links: - Copasi file of “Ortega2013 - Drug condition” - Copasi file of “Ortega2013 – No-drug condition”