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Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events.
J Neuroinflammation. 2019 Dec 30; 16(1):284.JN

Abstract

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.

Authors+Show Affiliations

Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA.Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536, USA. donna.wilcock@uky.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31888650

Citation

Weekman, Erica M., et al. "Time Course of Neuropathological Events in Hyperhomocysteinemic Amyloid Depositing Mice Reveals Early Neuroinflammatory Changes That Precede Amyloid Changes and Cerebrovascular Events." Journal of Neuroinflammation, vol. 16, no. 1, 2019, p. 284.
Weekman EM, Sudduth TL, Price BR, et al. Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events. J Neuroinflammation. 2019;16(1):284.
Weekman, E. M., Sudduth, T. L., Price, B. R., Woolums, A. E., Hawthorne, D., Seaks, C. E., & Wilcock, D. M. (2019). Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events. Journal of Neuroinflammation, 16(1), 284. https://doi.org/10.1186/s12974-019-1685-z
Weekman EM, et al. Time Course of Neuropathological Events in Hyperhomocysteinemic Amyloid Depositing Mice Reveals Early Neuroinflammatory Changes That Precede Amyloid Changes and Cerebrovascular Events. J Neuroinflammation. 2019 Dec 30;16(1):284. PubMed PMID: 31888650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events. AU - Weekman,Erica M, AU - Sudduth,Tiffany L, AU - Price,Brittani R, AU - Woolums,Abigail E, AU - Hawthorne,Danielle, AU - Seaks,Charles E, AU - Wilcock,Donna M, Y1 - 2019/12/30/ PY - 2019/05/09/received PY - 2019/12/19/accepted PY - 2020/1/1/entrez PY - 2020/1/1/pubmed PY - 2020/7/15/medline KW - Alzheimer’s disease KW - Astrocytic end-feet KW - Hyperhomocysteinemia KW - Microhemorrhage KW - Neuroinflammation KW - Vascular contributions to cognitive impairment and dementia SP - 284 EP - 284 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 16 IS - 1 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/31888650/Time_course_of_neuropathological_events_in_hyperhomocysteinemic_amyloid_depositing_mice_reveals_early_neuroinflammatory_changes_that_precede_amyloid_changes_and_cerebrovascular_events_ DB - PRIME DP - Unbound Medicine ER -