Proctor2012 - Role of Amyloid-beta dimers in aggregation formation

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Short description
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.

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Format
SBML (L2V4)
Related Publication
  • Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach.
  • Proctor CJ, Pienaar IS, Elson JL, Kirkwood TB
  • Molecular neurodegeneration , 7/ 2012 , Volume 7 , pages: 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
  • 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.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.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.
Contributors
Carole Proctor

Metadata information

is
BioModels Database MODEL1202290000
BioModels Database BIOMD0000000462
isDescribedBy
PubMed 22748062
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology amyloid-beta clearance
Gene Ontology inclusion body assembly
hasProperty
Human Disease Ontology Alzheimer's disease
Curation status
Curated
  • Model originally submitted by : Carole Proctor
  • Submitted: 29-Feb-2012 13:36:25
  • Last Modified: 10-Oct-2014 12:22:18
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 10-Oct-2014 12:22:18
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2012 - Role of Amyloid-beta dimers in aggregation formation
  • Version: 1 public model Download this version
    • Submitted on: 29-Feb-2012 13:36:25
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000462.xml.origin
Curator's comment:
(added: 20 Jun 2013, 16:27:29, updated: 20 Jun 2013, 16:27:29)
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.