Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events

BACKGROUND: Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomo...

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Autores principales: Weekman, Erica M., Sudduth, Tiffany L., Price, Brittani R., Woolums, Abigail E., Hawthorne, Danielle, Seaks, Charles E., Wilcock, Donna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937663/
https://www.ncbi.nlm.nih.gov/pubmed/31888650
http://dx.doi.org/10.1186/s12974-019-1685-z
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author Weekman, Erica M.
Sudduth, Tiffany L.
Price, Brittani R.
Woolums, Abigail E.
Hawthorne, Danielle
Seaks, Charles E.
Wilcock, Donna M.
author_facet Weekman, Erica M.
Sudduth, Tiffany L.
Price, Brittani R.
Woolums, Abigail E.
Hawthorne, Danielle
Seaks, Charles E.
Wilcock, Donna M.
author_sort Weekman, Erica M.
collection PubMed
description BACKGROUND: Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice. METHODS: APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze. RESULTS: Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature. CONCLUSIONS: The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.
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spelling pubmed-69376632019-12-31 Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events Weekman, Erica M. Sudduth, Tiffany L. Price, Brittani R. Woolums, Abigail E. Hawthorne, Danielle Seaks, Charles E. Wilcock, Donna M. J Neuroinflammation Research BACKGROUND: Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice. METHODS: APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze. RESULTS: Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature. CONCLUSIONS: The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points. BioMed Central 2019-12-30 /pmc/articles/PMC6937663/ /pubmed/31888650 http://dx.doi.org/10.1186/s12974-019-1685-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Weekman, Erica M.
Sudduth, Tiffany L.
Price, Brittani R.
Woolums, Abigail E.
Hawthorne, Danielle
Seaks, Charles E.
Wilcock, Donna M.
Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title_full Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title_fullStr Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title_full_unstemmed Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title_short Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
title_sort time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937663/
https://www.ncbi.nlm.nih.gov/pubmed/31888650
http://dx.doi.org/10.1186/s12974-019-1685-z
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