Thomas T, Rhodin J A, Sutton E T, Bryant M W, Price J M
Department of Anatomy, College of Medicine, University of South Florida, Tampa 33612, USA.
J Submicrosc Cytol Pathol. 1999 Oct;31(4):571-9.
Due to increases in life expectancy, women are living 30 years or more beyond menopause. This has led to an increasing interest in the association between postmenopausal estrogen deficiency and degenerative diseases associated with aging such as cardiovascular disease, osteoporosis and dementia. Women are two times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. The mechanism underlying the protective action of estrogen in AD is under active investigation. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. This rodent model allows live videomicroscopic recording and electron microscopic analysis of peripheral vascular disruption and inflammatory reaction triggered by A beta. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. Estrogen also protected the cerebral blood vessels from endothelial dysfunction induced by A beta. This novel protective effect of estrogen against A beta cytotoxicity in peripheral and cerebral vasculature may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.
由于预期寿命的增加，女性在绝经后仍能生活30年或更长时间。这使得人们对绝经后雌激素缺乏与衰老相关的退行性疾病（如心血管疾病、骨质疏松症和痴呆症）之间的关联越来越感兴趣。女性患晚发性阿尔茨海默病（AD）的可能性是年龄匹配男性的两倍。大量的观察报告和一些随机临床试验表明，雌激素替代疗法（ERT）可能会延缓绝经后女性痴呆症的发展和严重程度。雌激素在AD中的保护作用机制正在积极研究中。由淀粉样β蛋白（Aβ）等蛋白质异常沉积介导的慢性炎症反应是AD病理学的核心。我们在Aβ诱导的血管破坏和炎症反应的动物模型中研究了低剂量结合雌激素（倍美力）的作用。这种啮齿动物模型允许对Aβ引发的外周血管破坏和炎症反应进行实时视频显微镜记录和电子显微镜分析。雌激素可防止Aβ在血管中的沉积、内皮和血管壁破坏以及血浆渗漏、血小板和肥大细胞激活，以及炎症反应的特征：白细胞的黏附和迁移。当停止雌激素治疗时，这种有益效果就会消失。雌激素还能保护脑血管免受Aβ诱导的内皮功能障碍。雌激素对Aβ在外周和脑血管中的细胞毒性的这种新的保护作用可能有助于雌激素在AD和冠状动脉疾病中的治疗效果。
