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Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation.
J Cereb Blood Flow Metab. 2013 May; 33(5):708-15.JC

Abstract

Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders.

Authors+Show Affiliations

Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23361394

Citation

Sudduth, Tiffany L., et al. "Induction of Hyperhomocysteinemia Models Vascular Dementia By Induction of Cerebral Microhemorrhages and Neuroinflammation." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 33, no. 5, 2013, pp. 708-15.
Sudduth TL, Powell DK, Smith CD, et al. Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. J Cereb Blood Flow Metab. 2013;33(5):708-15.
Sudduth, T. L., Powell, D. K., Smith, C. D., Greenstein, A., & Wilcock, D. M. (2013). Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 33(5), 708-15. https://doi.org/10.1038/jcbfm.2013.1
Sudduth TL, et al. Induction of Hyperhomocysteinemia Models Vascular Dementia By Induction of Cerebral Microhemorrhages and Neuroinflammation. J Cereb Blood Flow Metab. 2013;33(5):708-15. PubMed PMID: 23361394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. AU - Sudduth,Tiffany L, AU - Powell,David K, AU - Smith,Charles D, AU - Greenstein,Abigail, AU - Wilcock,Donna M, Y1 - 2013/01/30/ PY - 2013/1/31/entrez PY - 2013/1/31/pubmed PY - 2013/7/3/medline SP - 708 EP - 15 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 33 IS - 5 N2 - Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/23361394/Induction_of_hyperhomocysteinemia_models_vascular_dementia_by_induction_of_cerebral_microhemorrhages_and_neuroinflammation_ L2 - https://journals.sagepub.com/doi/10.1038/jcbfm.2013.1?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -