title: Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID).
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.affiliation: University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Sudduth
authors.affiliation: University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Weekman
authors.affiliation: University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.
authors.forename: Brittani R
authors.initials: BR
authors.lastname: Price
authors.affiliation: University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Physiology, Lexington, KY 40536, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gooch
authors.affiliation: University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Woolums
authors.affiliation: 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.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
authors.affiliation: 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Wilcock
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology*; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000276:immunology / Q000473:pathology; D060825:Cognitive Dysfunction / Q000276:immunology* / Q000473:pathology*; D015140:Dementia, Vascular / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D016189:Dystrophin / Q000378:metabolism; D005911:Gliosis / Q000276:immunology / Q000473:pathology; D020138:Hyperhomocysteinemia / Q000276:immunology / Q000473:pathology; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098854:Kcnj10 Channel
chemical_list: D039481:CD11b Antigen; D016189:Dystrophin; C587672:IL1B protein, mouse; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D053583:Interleukin-1beta; D015850:Interleukin-6; D000098854:Kcnj10 Channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D014409:Tumor Necrosis Factor-alpha; C085339:apo-dystrophin 1; C577686:interleukin-6, mouse
keywords: astrocyte; cerebrovascular; dementia; microhemorrhage; neuroinflammation