Selective Astrocytic Endothelin-1 Overexpression Contributes to Dementia Associated with Ischemic Stroke by Exaggerating Astrocyte-Derived Amyloid Secretion. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Hung, Victor KL; Yeung, Patrick KK; Lai, Angela KW; Ho, Maggie CY; Lo, Amy CY; Chan, Kevin C; Wu, Ed XK; Chung, Stephen SM; Cheung, Chi W; Chung, Sookja K
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 35:Issue 10(2015)
• Page Start: 1687
• Page End: 1696
• Publication Date: 2015-10
• Subjects: Alzheimer's disease -- amyloidosis -- astrocytes -- endothelin-1 -- ischemic stroke; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1038/jcbfm.2015.109
• Languages: English
• ISSNs: 0271-678X

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- a, 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.