Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1

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Short description
Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1

This model is described in the article:

Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J.
J. Clin. Invest. 2011 Oct; 121(10): 3924-3931

Abstract:

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.

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Format
SBML (L2V4)
Related Publication
  • Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.
  • Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J
  • The Journal of clinical investigation , 10/ 2011 , Volume 121 , pages: 3924-3931
  • Department of Neurology, Neurodegeneration Research Laboratory, University of Rostock, Rostock, Germany.
  • In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.
Contributors
Felix Winter

Metadata information

is
BioModels Database MODEL1607270000
BioModels Database BIOMD0000000618
isDescribedBy
PubMed 21881209
isVersionOf
hasProperty
Human Disease Ontology Alzheimer's disease
Curation status
Curated
Original model(s)
http://files.kapora.de/krohn2011.xml
  • Model originally submitted by : Felix Winter
  • Submitted: Jul 27, 2016 9:31:33 AM
  • Last Modified: May 31, 2017 4:22:38 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: May 31, 2017 4:22:38 PM
    • Submitted by: Felix Winter
    • With comment: Current version of Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1
  • Version: 1 public model Download this version
    • Submitted on: Jul 27, 2016 9:31:33 AM
    • Submitted by: Felix Winter
    • With comment: Original import of ProtAggABC
Curator's comment:
(added: 06 Oct 2016, 15:18:42, updated: 06 Oct 2016, 15:18:42)
Figure 2 of the reference publication has been reproduced here. To obtain figure 2C and 2D, change c_T to 9.5 (11% increase of transport capacity). The paper use weeks as time scale, the model uses days instead of weeks (as the data was taken from mice at days 50, 100, etc - co-author of the paper and submitter of the model reported). The data was generated by simulating the model using SBMLSimulator 1.2.1, and gnuplot was used to generate the plots. Note: The SED-ML file that generates the curation figure can be downloaded from below link and can be run by loading it into SED-ML Web Tool - http://sysbioapps.dyndns.org/SED-ML_Web_Tools/.