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Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

Alzheimer’s disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors...

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Autores principales: Hoffman, Timothy E., Hanneman, William H., Moreno, Julie A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606936/
https://www.ncbi.nlm.nih.gov/pubmed/33195439
http://dx.doi.org/10.3389/fmolb.2020.590045
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author Hoffman, Timothy E.
Hanneman, William H.
Moreno, Julie A.
author_facet Hoffman, Timothy E.
Hanneman, William H.
Moreno, Julie A.
author_sort Hoffman, Timothy E.
collection PubMed
description Alzheimer’s disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors such as the tau protein. This multitude of age-related processes that cause neurons to change from healthy states to ones vulnerable to the damage seen in AD are difficult to simultaneously investigate and even more difficult to quantify. Here we aimed to diminish these gaps in our understanding of neuronal vulnerability in AD development by using simulation methods to theoretically quantify an array of cellular stress responses and signaling molecules. This temporally-descriptive molecular signature was produced using a novel multimethod simulation approach pioneered by our laboratory for biological research; this methodology combines hierarchical agent-based processes and continuous equation-based modeling in the same interface, all while maintaining intrinsic distributions that emulate natural biological stochasticity. The molecular signature was validated for a normal organismal aging trajectory using experimental longitudinal data from Caenorhabditis elegans and rodent studies. In addition, we have further predicted this aging molecular signature for cells impacted by the pathogenic tau protein, giving rise to distinct stress response conditions needed for cytoprotective aging. Interestingly, our simulation experiments showed that oxidative stress signaling (via daf-16 and skn-1 activities) does not substantially protect cells from all the early stressors of aging, but that it is essential in preventing a late-life degenerative cellular phenotype. Together, our simulation experiments aid in elucidating neurodegenerative triggers in the onset of AD for different genetic conditions. The long-term goal of this work is to provide more detailed diagnostic and prognostic tools for AD development and progression, and to provide more comprehensive preventative measures for this disease.
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spelling pubmed-76069362020-11-13 Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation Hoffman, Timothy E. Hanneman, William H. Moreno, Julie A. Front Mol Biosci Molecular Biosciences Alzheimer’s disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors such as the tau protein. This multitude of age-related processes that cause neurons to change from healthy states to ones vulnerable to the damage seen in AD are difficult to simultaneously investigate and even more difficult to quantify. Here we aimed to diminish these gaps in our understanding of neuronal vulnerability in AD development by using simulation methods to theoretically quantify an array of cellular stress responses and signaling molecules. This temporally-descriptive molecular signature was produced using a novel multimethod simulation approach pioneered by our laboratory for biological research; this methodology combines hierarchical agent-based processes and continuous equation-based modeling in the same interface, all while maintaining intrinsic distributions that emulate natural biological stochasticity. The molecular signature was validated for a normal organismal aging trajectory using experimental longitudinal data from Caenorhabditis elegans and rodent studies. In addition, we have further predicted this aging molecular signature for cells impacted by the pathogenic tau protein, giving rise to distinct stress response conditions needed for cytoprotective aging. Interestingly, our simulation experiments showed that oxidative stress signaling (via daf-16 and skn-1 activities) does not substantially protect cells from all the early stressors of aging, but that it is essential in preventing a late-life degenerative cellular phenotype. Together, our simulation experiments aid in elucidating neurodegenerative triggers in the onset of AD for different genetic conditions. The long-term goal of this work is to provide more detailed diagnostic and prognostic tools for AD development and progression, and to provide more comprehensive preventative measures for this disease. Frontiers Media S.A. 2020-10-20 /pmc/articles/PMC7606936/ /pubmed/33195439 http://dx.doi.org/10.3389/fmolb.2020.590045 Text en Copyright © 2020 Hoffman, Hanneman and Moreno. 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(s) 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 Molecular Biosciences
Hoffman, Timothy E.
Hanneman, William H.
Moreno, Julie A.
Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title_full Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title_fullStr Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title_full_unstemmed Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title_short Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
title_sort network simulations reveal molecular signatures of vulnerability to age-dependent stress and tau accumulation
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606936/
https://www.ncbi.nlm.nih.gov/pubmed/33195439
http://dx.doi.org/10.3389/fmolb.2020.590045
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