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BIOMD0000000462 - Proctor2012 - Role of Amyloid-beta dimers in aggregation formation

 

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Reference Publication
Publication ID: 22748062
Proctor CJ, Pienaar IS, Elson JL, Kirkwood TB.
Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach.
Mol Neurodegener 2012; 7: 32
Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom. carole.proctor@ncl.ac.uk  [more]
Model
Original Model: BIOMD0000000462.xml.origin
Submitter: Carole Proctor
Submission ID: MODEL1202290000
Submission Date: 29 Feb 2012 13:36:25 UTC
Last Modification Date: 07 Aug 2014 15:34:37 UTC
Creation Date: 06 Jun 2013 19:51:15 UTC
Encoders:  Carole Proctor
   Vijayalakshmi Chelliah
set #1
bqbiol:hasProperty Human Disease Ontology DOID:10652
set #2
bqbiol:hasTaxon Taxonomy Homo sapiens
set #3
bqbiol:isVersionOf Gene Ontology inclusion body assembly
Gene Ontology beta-amyloid clearance
Notes
Proctor2012 - Amyloid-beta aggregation

This model supports the current thinking that levels of dimers are important in initiating the aggregation process.

This model is described in the article:

Proctor CJ, Pienaar IS, Elson JL, Kirkwood TB
Molecular Neurodegeneration. 2012; 7:32

Abstract:

BACKGROUND: Alzheimer's disease (AD) is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß), particularly Aß₄₂, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß₄₂ immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool's utility, we developed computer simulation models to examine Aß₄₂ turnover and its aggregation in detail and to test the effect of immunization against Aß dimers.

RESULTS: Our model demonstrates for the first time that even a slight decrease in the clearance rate of Aß₄₂ monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of Aβ are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present.

CONCLUSION: Our model supports the current thinking that levels of dimers are important in initiating the aggregation process. Although substantial knowledge exists regarding the process, no therapeutic intervention is on offer that reliably decreases disease burden in AD patients. Computer modelling could serve as one of a number of tools to examine both the validity of reliable biomarkers and aid the discovery of successful intervention strategies.

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: 22748062 Submission Date: 29 Feb 2012 13:36:25 UTC Last Modification Date: 07 Aug 2014 15:34:37 UTC Creation Date: 06 Jun 2013 19:51:15 UTC
Mathematical expressions
Reactions
Abetaproduction AbetaDegradation AbetaDimerisation AbetaDedimerisation
AbetaPlaqueFormation AbetaPlaqueGrowth AbetaDisaggregation NepDegradation
Physical entities
Compartments Species
cell AbetaMonomer AbetaDimer AbetaPlaque
Source Sink Neprilysin
Global parameters
kprod kdeg kdimer kdedimer
kdisagg kpf kpg kpghalf
kdegNep      
Reactions (8)
 
 Abetaproduction [Source] → [AbetaMonomer];   {Source}
 
 AbetaDegradation [AbetaMonomer] + [Neprilysin] → [Sink] + [Neprilysin];   {AbetaMonomer} , {Neprilysin}
 
 AbetaDimerisation 2.0 × [AbetaMonomer] → [AbetaDimer];   {AbetaMonomer}
 
 AbetaDedimerisation [AbetaDimer] → 2.0 × [AbetaMonomer];   {AbetaDimer}
 
 AbetaPlaqueFormation 2.0 × [AbetaDimer] → 4.0 × [AbetaPlaque];   {AbetaDimer}
 
 AbetaPlaqueGrowth [AbetaMonomer] + [AbetaPlaque] → 2.0 × [AbetaPlaque];   {AbetaMonomer} , {AbetaPlaque}
 
 AbetaDisaggregation [AbetaPlaque] → [AbetaMonomer];   {AbetaPlaque}
 
 NepDegradation [Neprilysin] → [Sink];   {Neprilysin}
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 AbetaMonomer
Compartment: cell
Initial amount: 0.0
 
 AbetaDimer
Compartment: cell
Initial amount: 0.0
 
 AbetaPlaque
Compartment: cell
Initial amount: 0.0
 
 Source
Compartment: cell
Initial amount: 1.0
Constant
 
 Sink
Compartment: cell
Initial amount: 1.0
Constant
 
 Neprilysin
Compartment: cell
Initial amount: 1000.0
 
Global Parameters (9)
 
   kprod
Value: 1.86E-5
Constant
 
   kdeg
Value: 2.1E-5
Constant
 
   kdimer
Value: 1.1783E-7
Constant
 
   kdedimer
Value: 8.4655E-6
Constant
 
   kdisagg
Value: 5.4357E-5
Constant
 
   kpf
Value: 2.785E-6
Constant
 
   kpg
Value: 0.00574
Constant
 
   kpghalf
Value: 4.0
Constant
 
   kdegNep
Value: 1.8E-10
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000462

Curator's comment: (updated: 20 Jun 2013 16:27:29 BST)

Figures 5A and 5B of the reference publication has been reproduced using Copasi v4.8 (Build 35). Method used: Stochastic (Direct). As the plot obtained is by stochastic simulation, it slightly varies from that of the paper.

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