title: Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion.
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.
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.
authors.forename: Victor K L
authors.initials: VK
authors.lastname: Hung
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.|School of Biomedical Sciences, The University of Hong Kong, HKSAR, China.
authors.forename: Patrick K K
authors.initials: PK
authors.lastname: Yeung
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.
authors.forename: Angela K W
authors.initials: AK
authors.lastname: Lai
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ho
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.
authors.forename: Amy C Y
authors.initials: AC
authors.lastname: Lo
authors.affiliation: University of Biomedical Imaging and Signal Processing, The University of Hong Kong, HKSAR, China.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Chan
authors.affiliation: University of Biomedical Imaging and Signal Processing, The University of Hong Kong, HKSAR, China.
authors.forename: Ed X K
authors.initials: EX
authors.lastname: Wu
authors.affiliation: Department of Physiology, The University of Hong Kong, HKSAR, China.
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China.|Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China.
authors.forename: Chi W
authors.initials: CW
authors.lastname: Cheung
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China.|School of Biomedical Sciences, The University of Hong Kong, HKSAR, China.|Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China.|The State Key Laboratory of Pharmaceutical Biotechnology, Zhuhai, Guandong, China.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
mesh_terms: D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001929:Brain Edema / Q000150:complications / Q000523:psychology; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism* / Q000523:psychology; D003071:Cognition; D003704:Dementia / Q000209:etiology* / Q000378:metabolism* / Q000523:psychology; D019332:Endothelin-1 / Q000096:biosynthesis*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000209:etiology / Q000523:psychology
chemical_list: D058227:Amyloidogenic Proteins; D019332:Endothelin-1