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Investigating interventions in Alzheimer's disease with computer simulation models

Investigating interventions in Alzheimer's disease with computer simulation models
Investigating interventions in Alzheimer's disease with computer simulation models
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 (A?) 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 A? and then demonstrate the effects of this intervention on soluble A?, 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 A?, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against A?. Since, soluble A?, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against A? may not be effective unless it is performed very early in the disease process or combined with other therapies.
1932-6203
e73631
Proctor, Carole J.
ebe130d6-04d9-407c-b2b5-91594c657871
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Gray, Douglas A.
5498ff7e-2d04-4105-b6ed-b1320d9193f2
Nicoll, James A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Proctor, Carole J.
ebe130d6-04d9-407c-b2b5-91594c657871
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Gray, Douglas A.
5498ff7e-2d04-4105-b6ed-b1320d9193f2
Nicoll, James A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed

Proctor, Carole J., Boche, Delphine, Gray, Douglas A. and Nicoll, James A.R. (2013) Investigating interventions in Alzheimer's disease with computer simulation models. PLoS ONE, 8 (9), e73631. (doi:10.1371/journal.pone.0073631). (PMID:24098635)

Record type: Article

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 (A?) 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 A? and then demonstrate the effects of this intervention on soluble A?, 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 A?, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against A?. Since, soluble A?, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against A? may not be effective unless it is performed very early in the disease process or combined with other therapies.

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Published date: 16 September 2013
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 358853
URI: http://eprints.soton.ac.uk/id/eprint/358853
ISSN: 1932-6203
PURE UUID: 71f1b4b9-a9ac-4546-9106-698a0083acb8
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X
ORCID for James A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 14 Oct 2013 13:43
Last modified: 17 Dec 2019 01:52

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Contributors

Author: Carole J. Proctor
Author: Delphine Boche ORCID iD
Author: Douglas A. Gray

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