Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (deterministic version)

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Short description
Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (deterministic version)

Extension of a previously published stochastic model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau ( BIOMD0000000286, BIOMD0000000462)) to include the main processes involved in passive and active immunisation against Aβ and then to demonstrate the effects of this intervention on soluble Aβ. This is the deterministic version of the model, the stochastic version is BIOMD0000000634.

This model is described in the article:

Proctor CJ, Boche D, Gray DA, Nicoll JA.
PLoS ONE 2013; 8(9): e73631

Abstract:

Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.

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Format
SBML (L2V4)
Related Publication
  • Investigating interventions in Alzheimer's disease with computer simulation models.
  • Proctor CJ, Boche D, Gray DA, Nicoll JA
  • PloS one , 0/ 2013 , Volume 8 , pages: e73631
  • Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.
Contributors
Carole Proctor

Metadata information

is
BioModels Database MODEL1212030000
BioModels Database BIOMD0000000488
isDerivedFrom
BioModels Database BIOMD0000000286
BioModels Database BIOMD0000000462
isDescribedBy
PubMed 24098635
hasTaxon
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology Alzheimer's disease
Mathematical Modelling Ontology Ordinary differential equation model
hasPart
Pathway Ontology Alzheimer disease pathway
Curation status
Curated
Original model(s)
Proctor2012_GSK3_p53_AlzheimerDisease_Immunisation_Day4
  • Model originally submitted by : Carole Proctor
  • Submitted: 03-Dec-2012 09:44:56
  • Last Modified: 08-May-2017 18:28:04
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-May-2017 18:28:04
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (deterministic version)
  • Version: 1 public model Download this version
    • Submitted on: 03-Dec-2012 09:44:56
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000488.xml.origin
Curator's comment:
(added: 26 Sep 2013, 18:06:33, updated: 26 Sep 2013, 18:06:33)
Figure 2B (immunisation administered on day 4) of the reference publication has been reproduced here. The model time is in seconds. So, to obtain the result for 12 days, the simulation should be run for 1036800 sec (=12 days). The model was simulated using Copasi v4.10 (Build 55). The plot was generated using Gnuplot.