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Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach

Alzheimer's Disease (AD) is the most common neuro-degenerative disorder in the elderly that leads to dementia. The hallmark of AD is senile lesions made by abnormal aggregation of amyloid beta in extracellular space of brain. One of the challenges in AD treatment is to better understand the mec...

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Autores principales: Ashraf, Javaria, Ahmad, Jamil, Ali, Amjad, Ul-Haq, Zaheer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974338/
https://www.ncbi.nlm.nih.gov/pubmed/29875647
http://dx.doi.org/10.3389/fninf.2018.00026
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author Ashraf, Javaria
Ahmad, Jamil
Ali, Amjad
Ul-Haq, Zaheer
author_facet Ashraf, Javaria
Ahmad, Jamil
Ali, Amjad
Ul-Haq, Zaheer
author_sort Ashraf, Javaria
collection PubMed
description Alzheimer's Disease (AD) is the most common neuro-degenerative disorder in the elderly that leads to dementia. The hallmark of AD is senile lesions made by abnormal aggregation of amyloid beta in extracellular space of brain. One of the challenges in AD treatment is to better understand the mechanism of action of key proteins and their related pathways involved in neuronal cell death in order to identify adequate therapeutic targets. This study focuses on the phenomenon of aggregation of amyloid beta into plaques by considering the signal transduction pathways of Calpain-Calpastatin (CAST) regulation system and Amyloid Precursor Protein (APP) processing pathways along with Ca(2+) channels. These pathways are modeled and analyzed individually as well as collectively through Stochastic Petri Nets for comprehensive analysis and thorough understating of AD. The model predicts that the deregulation of Calpain activity, disruption of Calcium homeostasis, inhibition of CAST and elevation of abnormal APP processing are key cytotoxic events resulting in an early AD onset and progression. Interestingly, the model also reveals that plaques accumulation start early (at the age of 40) in life but symptoms appear late. These results suggest that the process of neuro-degeneration can be slowed down or paused by slowing down the degradation rate of Calpain-CAST Complex. In the light of this study, the suggestive therapeutic strategy might be the prevention of the degradation of Calpain-CAST complexes and the inhibition of Calpain for the treatment of neurodegenerative diseases such as AD.
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spelling pubmed-59743382018-06-06 Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach Ashraf, Javaria Ahmad, Jamil Ali, Amjad Ul-Haq, Zaheer Front Neuroinform Neuroscience Alzheimer's Disease (AD) is the most common neuro-degenerative disorder in the elderly that leads to dementia. The hallmark of AD is senile lesions made by abnormal aggregation of amyloid beta in extracellular space of brain. One of the challenges in AD treatment is to better understand the mechanism of action of key proteins and their related pathways involved in neuronal cell death in order to identify adequate therapeutic targets. This study focuses on the phenomenon of aggregation of amyloid beta into plaques by considering the signal transduction pathways of Calpain-Calpastatin (CAST) regulation system and Amyloid Precursor Protein (APP) processing pathways along with Ca(2+) channels. These pathways are modeled and analyzed individually as well as collectively through Stochastic Petri Nets for comprehensive analysis and thorough understating of AD. The model predicts that the deregulation of Calpain activity, disruption of Calcium homeostasis, inhibition of CAST and elevation of abnormal APP processing are key cytotoxic events resulting in an early AD onset and progression. Interestingly, the model also reveals that plaques accumulation start early (at the age of 40) in life but symptoms appear late. These results suggest that the process of neuro-degeneration can be slowed down or paused by slowing down the degradation rate of Calpain-CAST Complex. In the light of this study, the suggestive therapeutic strategy might be the prevention of the degradation of Calpain-CAST complexes and the inhibition of Calpain for the treatment of neurodegenerative diseases such as AD. Frontiers Media S.A. 2018-05-23 /pmc/articles/PMC5974338/ /pubmed/29875647 http://dx.doi.org/10.3389/fninf.2018.00026 Text en Copyright © 2018 Ashraf, Ahmad, Ali and Ul-Haq. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Ashraf, Javaria
Ahmad, Jamil
Ali, Amjad
Ul-Haq, Zaheer
Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title_full Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title_fullStr Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title_full_unstemmed Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title_short Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach
title_sort analyzing the behavior of neuronal pathways in alzheimer's disease using petri net modeling approach
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974338/
https://www.ncbi.nlm.nih.gov/pubmed/29875647
http://dx.doi.org/10.3389/fninf.2018.00026
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