Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 21, Issue 3, Pages 887-896Publisher
IOS PRESS
DOI: 10.3233/JAD-2010-091486
Keywords
Endothelin-1; microvessels; neuroprotective; thrombin
Categories
Funding
- Shirley and Mildred Garrison Chair in Aging
- NATIONAL INSTITUTE ON AGING [R01AG028367, R01AG015964, R01AG020569] Funding Source: NIH RePORTER
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The vasoactive protein endothelin-1 (ET-1) is produced by vascular endothelial cells and participates in the regulation of vascular inflammation. We have previously documented that the cerebral microvasculature is a source of inflammatory proteins and a likely contributor to the pathogenesis of Alzheimer's disease (AD). In this study, we (a) compare expression of ET-1 in brain microvessels isolated from AD and control brains; (b) determine thrombin regulation of ET-1 synthesis and release in brain endothelial cells; and (c) assess the effects of ET-1 on neuronal viability in vitro. Western blot analysis indicates a significantly higher level of ET-1 in AD vessels compared to vessels from age-matched controls. ET-1 expression and secretion are both induced by the inflammatory and neurotoxic protein thrombin. Pretreatment of neuronal cultures with ET-1 significantly increases neuronal survival when cells are challenged with oxidative stress (H2O2) or thrombin. The protective effect of ET-1 is blocked by incubation with an inhibitor of the c-Jun kinase (JNK) cascade. These data demonstrate that in the brain microvasculature dysfunctional or stressed endothelial cells express ET-1 and that this protein promotes the survival of brain neurons exposed to injury.
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