Dataset Information

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

ABSTRACT: Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (stochastic version) Extension of a previously published stochastic model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (A β) and the micro-tubular binding protein tau ( BIOMD0000000286, BIOMD0000000462)) to include the main processes involved in passive and active immunisation against A β and then to demonstrate the effects of this intervention on soluble A β. This is the stochastic version of the model, the deterministic version is BIOMD0000000488. This model is described in the article: Investigating interventions in Alzheimer's disease with computer simulation models. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000634. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. 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.

DISEASE(S): Alzheimer's Disease

SUBMITTER: Carole Proctor

PROVIDER: BIOMD0000000634 | BioModels | 2024-09-02

REPOSITORIES: BioModels

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	BIOMD0000000634?filename=BIOMD0000000634-biopax2.owl	Owl
	BIOMD0000000634?filename=BIOMD0000000634-biopax3.owl	Owl
	BIOMD0000000634?filename=BIOMD0000000634-matlab.m	Other
	BIOMD0000000634?filename=BIOMD0000000634.m	Other
	BIOMD0000000634?filename=BIOMD0000000634.ode	Other

Items per page:

1 - 5 of 14

Publications

Investigating interventions in Alzheimer's disease with computer simulation models.

Proctor Carole J CJ Boche Delphine D Gray Douglas A DA Nicoll James A R JA

PloS one 20130916 9

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 sti ...[more]

PMID: 24098635

Similar Datasets

Project 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: Investigating interventions in Alzheimer's disease with computer simulation models. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000488. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. 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.

Project description:Alzheimer’s disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The APOE ε2 encoding apolipoprotein E (APOE2) is a protective allele against AD among the three genotypes (APOE ε2, ε3, ε4), while APOE4 is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4. Gene therapy that increases APOE2 levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based APOE2 gene delivery influences Aβ)-related pathologies in amyloid model AppNL-G-F knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy. Furthermore, in the AppNL-G-F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.