Dataset Information

Proctor2012 - Role of Amyloid-beta dimers in aggregation formation

ABSTRACT: 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: 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. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000462 . 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: BIOMD0000000462 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000462?filename=BIOMD0000000462-biopax2.owl	Owl
	BIOMD0000000462?filename=BIOMD0000000462-biopax3.owl	Owl
	BIOMD0000000462?filename=BIOMD0000000462.m	Other
	BIOMD0000000462?filename=BIOMD0000000462.pdf	Pdf
	BIOMD0000000462?filename=BIOMD0000000462.png	Other

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Publications

Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach.

Proctor Carole J CJ Pienaar Ilse Sanet IS Elson Joanna L JL Kirkwood Thomas B L TB

Molecular neurodegeneration 20120702

<h4>Background</h4>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 character ...[more]

PMID: 22748062

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Project description:Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 Abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD. This model is hosted on BioModels Database and identified by: BIOMD0000000618. 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: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.