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

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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
administrator, 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
Name Description Size Actions

Model files

BIOMD0000000618_url.xml SBML L2V4 representation of Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 135.52 KB Preview | Download

Additional files

BIOMD0000000618-biopax3.owl Auto-generated BioPAX (Level 3) 12.36 KB Preview | Download
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BIOMD0000000618.pdf Auto-generated PDF file 221.33 KB Preview | Download
BIOMD0000000618_SED-ML.xml This SED-ML file allow you to reproduce the curation results (Figures 2A-D), for example, by loading it into SED-ML Web Tools (http://sysbioapps.dyndns.org/SED-ML_Web_Tools/). 4.05 KB Preview | Download
BIOMD0000000618_urn.xml Auto-generated SBML file with URNs 135.42 KB Preview | Download
BIOMD0000000618.m Auto-generated Octave file 17.79 KB Preview | Download
BIOMD0000000618-biopax2.owl Auto-generated BioPAX (Level 2) 7.50 KB Preview | Download
BIOMD0000000618.vcml Auto-generated VCML file 900.00 bytes Preview | Download
BIOMD0000000618.png Auto-generated Reaction graph (PNG) 4.27 KB Preview | Download
BIOMD0000000618.sci Auto-generated Scilab file 11.25 KB Preview | Download
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  • Model originally submitted by : Felix Winter
  • Submitted: Jul 27, 2016 9:31:33 AM
  • Last Modified: Dec 21, 2018 6:18:37 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 6:18:37 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: BIOMD0000000618_SED-ML.xml
  • 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/.