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Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID).
Neuroscience. 2017 01 26; 341:42-51.N

Abstract

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent co-morbidity with AD. Despite its prevalence, little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. Astrocytic end-feet almost completely surround intraparenchymal blood vessels in the brain and express a variety of channels and markers indicative of their specialized functions in the maintenance of ionic and osmotic homeostasis and gliovascular signaling. These functions are mediated by end-foot enrichment of the aquaporin 4 water channel (AQP4), the inward rectifying potassium channel Kir4.1 and the calcium-dependent potassium channel MaxiK. Using our hyperhomocysteinemia (HHcy) model of VCID we examined the time-course of astrocytic end-foot changes along with cognitive and neuroinflammatory outcomes. We found that there were significant astrocytic end-foot disruptions in the HHcy model. AQP4 becomes dislocalized from the end-feet, there is a loss of Kir4.1 and MaxiK protein expression, as well as a loss of the Dp71 protein known to anchor the Kir4.1, MaxiK and AQP4 channels to the end-foot membrane. Neuroinflammation occurs prior to the astrocytic changes, while cognitive impairment continues to decline with the exacerbation of the astrocytic changes. We have previously reported similar astrocytic changes in models of cerebral amyloid angiopathy (CAA) and therefore, we believe astrocytic end-foot disruption could represent a common cellular mechanism of VCID and may be a target for therapeutic development.

Authors+Show Affiliations

University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Pharmacology and Nutritional Sciences, Lexington, KY 40536, USA.University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA. Electronic address: donna.wilcock@uky.edu.

Pub Type(s)

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

Language

eng

PubMed ID

27890830

Citation

Sudduth, Tiffany L., et al. "Time-course of Glial Changes in the Hyperhomocysteinemia Model of Vascular Cognitive Impairment and Dementia (VCID)." Neuroscience, vol. 341, 2017, pp. 42-51.
Sudduth TL, Weekman EM, Price BR, et al. Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience. 2017;341:42-51.
Sudduth, T. L., Weekman, E. M., Price, B. R., Gooch, J. L., Woolums, A., Norris, C. M., & Wilcock, D. M. (2017). Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience, 341, 42-51. https://doi.org/10.1016/j.neuroscience.2016.11.024
Sudduth TL, et al. Time-course of Glial Changes in the Hyperhomocysteinemia Model of Vascular Cognitive Impairment and Dementia (VCID). Neuroscience. 2017 01 26;341:42-51. PubMed PMID: 27890830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). AU - Sudduth,Tiffany L, AU - Weekman,Erica M, AU - Price,Brittani R, AU - Gooch,Jennifer L, AU - Woolums,Abigail, AU - Norris,Christopher M, AU - Wilcock,Donna M, Y1 - 2016/11/25/ PY - 2016/07/28/received PY - 2016/11/10/revised PY - 2016/11/17/accepted PY - 2016/11/29/pubmed PY - 2017/7/4/medline PY - 2016/11/29/entrez KW - astrocyte KW - cerebrovascular KW - dementia KW - microhemorrhage KW - neuroinflammation SP - 42 EP - 51 JF - Neuroscience JO - Neuroscience VL - 341 N2 - Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent co-morbidity with AD. Despite its prevalence, little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. Astrocytic end-feet almost completely surround intraparenchymal blood vessels in the brain and express a variety of channels and markers indicative of their specialized functions in the maintenance of ionic and osmotic homeostasis and gliovascular signaling. These functions are mediated by end-foot enrichment of the aquaporin 4 water channel (AQP4), the inward rectifying potassium channel Kir4.1 and the calcium-dependent potassium channel MaxiK. Using our hyperhomocysteinemia (HHcy) model of VCID we examined the time-course of astrocytic end-foot changes along with cognitive and neuroinflammatory outcomes. We found that there were significant astrocytic end-foot disruptions in the HHcy model. AQP4 becomes dislocalized from the end-feet, there is a loss of Kir4.1 and MaxiK protein expression, as well as a loss of the Dp71 protein known to anchor the Kir4.1, MaxiK and AQP4 channels to the end-foot membrane. Neuroinflammation occurs prior to the astrocytic changes, while cognitive impairment continues to decline with the exacerbation of the astrocytic changes. We have previously reported similar astrocytic changes in models of cerebral amyloid angiopathy (CAA) and therefore, we believe astrocytic end-foot disruption could represent a common cellular mechanism of VCID and may be a target for therapeutic development. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/27890830/Time_course_of_glial_changes_in_the_hyperhomocysteinemia_model_of_vascular_cognitive_impairment_and_dementia__VCID__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(16)30645-5 DB - PRIME DP - Unbound Medicine ER -