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BIOMD0000000553 - Ehrenstein1997 - The choline-leakage hypothesis in Alzheimer's disease

 

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Reference Publication
Publication ID: 9284295
Ehrenstein G, Galdzicki Z, Lange GD.
The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer's disease.
Biophys. J. 1997 Sep; 73(3): 1276-1280
Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. gerry@helix.nih.gov  [more]
Model
Original Model: BIOMD0000000553.origin
Submitter: Audald Lloret i Villas
Submission ID: MODEL1410200000
Submission Date: 20 Oct 2014 13:23:02 UTC
Last Modification Date: 17 Mar 2015 17:01:06 UTC
Creation Date: 20 Oct 2014 14:38:11 UTC
Encoders:  Audald Lloret i Villas
set #1
bqbiol:hasVersion Human Disease Ontology Alzheimer's disease
set #2
bqbiol:isVersionOf Gene Ontology acetylcholine biosynthetic process
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Ehrenstein1997 - The choline-leakage hypothesis in Alzheimer's disease

This model is described in the article:

Ehrenstein G, Galdzicki Z, Lange GD.
Biophys. J. 1997 Sep; 73(3): 1276-1280

Abstract:

We present a hypothesis for the loss of acetylcholine in Alzheimer's disease that is based on two recent experimental results: that beta-amyloid causes leakage of choline across cell membranes and that decreased production of acetylcholine increases the production of beta-amyloid. According to the hypothesis, an increase in beta-amyloid concentration caused by proteolysis of the amyloid precursor protein results in an increase in the leakage of choline out of cells. This leads to a reduction in intracellular choline concentration and hence a reduction in acetylcholine production. The reduction in acetylcholine production, in turn, causes an increase in the concentration of beta-amyloid. The resultant positive feedback between decreased acetylcholine and increased beta-amyloid accelerates the loss of acetylcholine. We compare the predictions of the choline-leakage hypothesis with a number of experimental observations. We also approximate it with a pair of ordinary differential equations. The solutions of these equations indicate that the loss of acetylcholine is very sensitive to the initial rate of beta-amyloid production.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 9284295 Submission Date: 20 Oct 2014 13:23:02 UTC Last Modification Date: 17 Mar 2015 17:01:06 UTC Creation Date: 20 Oct 2014 14:38:11 UTC
Mathematical expressions
Reactions
Loss of intracellular choline Abeta formation from APP Effect of extracellular ACh Decrease in the extracellular concentration of beta-amyloid
Rules
Assignment Rule (variable: aRel)      
Physical entities
Compartments Species
Brain a b aRel
Global parameters
k1 k2 k3 k4
Reactions (4)
 
 Loss of intracellular choline [a] → ;   {b} , {a} , {b}
 
 Abeta formation from APP  → [b];  
 
 Effect of extracellular ACh [b] → ;   {a} , {a}
 
 Decrease in the extracellular concentration of beta-amyloid [b] → ;   {b}
 
Rules (1)
 
 Assignment Rule (name: aRel) aRel = a/50
 
Functions (4)
 
 Constant flux (irreversible) lambda(v, v)
 
 Loss of intracellular choline lambda(k1, a, b, k1*a*b)
 
 Effect of extracellular ACh lambda(k3, a, k3*a)
 
 Decrease in the extracellular concentration of beta-amyloid lambda(k4, b, k4*b)
 
 Brain Spatial dimensions: 3.0  Compartment size: 1.0
 
 a
Compartment: Brain
Initial concentration: 50.0
 
 b
Compartment: Brain
Initial concentration: 0.0
 
  aRel
Compartment: Brain
Initial concentration: 1.0
 
Global Parameters (4)
 
 k1
Value: 0.007
Constant
 
 k2
Value: 0.33
Constant
 
 k3
Value: 0.0042
Constant
 
 k4
Value: 0.01
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000553

Curator's comment: (updated: 20 Oct 2014 16:21:26 GMT)

Figure 1 has been reproduced here. Time course of the decline in acetylcholine is plotted ranging different values for k2 parameter.

The simulation was done using Copasi v4.12 (Build 81) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link.

Additional file(s)
  • Ehrenstein1997 - The choline-leakage hypothesis in Alzheimer's disease:
    Copasi file of the model
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