Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion
| Autor: | Amy C. Y. Lo, Angela K. W. Lai, Ed X. Wu, Chi W Cheung, Stephen S.M. Chung, Patrick Ka Kit Yeung, Sookja K. Chung, Maggie C. Y. Ho, Victor K L Hung, Kevin C. Chan |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Genetically modified mouse medicine.medical_specialty Ischemia Amyloidogenic Proteins Brain Edema Mice Transgenic Hippocampus Brain Ischemia Mice Cognition Downregulation and upregulation Internal medicine Animals Humans Medicine Dementia Hypoxia Brain Maze Learning Cognitive deficit Memory Disorders Endothelin-1 business.industry Infarction Middle Cerebral Artery Hypoxia (medical) medicine.disease Endothelin 1 Endocrinology medicine.anatomical_structure Neurology Ischemic Attack Transient Astrocytes Original Article Neurology (clinical) Nervous System Diseases medicine.symptom Cardiology and Cardiovascular Medicine business Neuroscience Astrocyte |
| Popis: | 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 astrocytederived amyloid production. link_to_OA_fulltext |
| Databáze: | OpenAIRE |
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