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- Title
Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion.
- Authors
Hung, Victor K L; Yeung, Patrick K K; Lai, Angela K W; Ho, Maggie C Y; Lo, Amy C Y; Chan, Kevin C; Wu, Ed X K; Chung, Stephen S M; Cheung, Chi W; Chung, Sookja K
- Abstract
Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.
- Subjects
ASTROCYTES; PREPROENDOTHELIN; GENE expression; DEMENTIA; STROKE treatment; AMYLOID
- Publication
Journal of Cerebral Blood Flow & Metabolism, 2015, Vol 35, Issue 10, p1687
- ISSN
0271-678X
- Publication type
Article
- DOI
10.1038/jcbfm.2015.109