CEREBROVASCULAR SIGNAL PATHWAYS IN AGING AND ALZHEIMER'S

这项研究的长期目标是确定和描述 脑功能、生化和分子异常 衰老和痴呆的微循环。血脑检查 屏障功能是理解慢性阻塞性肺疾病发病机制的关键 衰老和阿尔茨海默病中的神经细胞死亡 脑内皮细胞对神经元离子和营养的主动调节 微环境。虽然血脑的范围和重要性 衰老和阿尔茨海默病中的屏障异常 有争议的，相当多的证据表明， 血脑屏障。我们的假设是， 微血管受体介导的信号通路可能参与了 阿尔茨海默病患者血脑屏障反应性改变。 血脑屏障的异常可能是年龄和/或阿尔茨海默病- 相关的。因此，阿尔茨海默病患者的微血管反应性 年龄匹配的非痴呆老年患者的疾病和I成人对照 将对患者进行评估。此外，在年轻人和老年人中的实验 啮齿动物是必要的，是一种即时和现成的材料来源 可以评估哪些方法、存储和年龄相关的变化。 具体来说，微血管肾上腺素能和胆碱能受体， 腺苷环化酶和蛋白激酶C在基础和激动剂下 刺激条件，将从上述组别中依次评定 以确定与年龄和疾病相关的改变。实验是 计划分析，(1)使用放射性配基的受体结合参数 结合技术，受体连接的Gs通过重组在 S_(49)Cyc(G蛋白缺陷型)细胞，以及毒素诱导的Gs和GI水平 核糖化；(2)cAMP测定腺苷环化酶水平 蓄积和[~3H]Forskolin结合、特异度和活性 用磷酸蛋白分析酶，用RNA印迹法检测mRNA的表达 分析；以及(3)蛋白激酶C活性、基础分布和 激动剂刺激的易位，Western blotts的亚型水平，以及 由Northern分析得出的消息级别。结果将定义 细胞内信号转导通路的功能与调控 血脑屏障，可能为糖尿病的发生发展提供基础。 改善脑血管疾病的合理治疗策略 阿尔茨海默病的神经元功能。

The long-term goal of this study is to identify and characterize functional, biochemical and molecular abnormalities of the cerebral microcirculation in aging and dementia. Examination of blood-brain barrier function is critical to understanding the pathogenesis of neuronal cell death in aging and Alzheimer's Disease because the cerebral endothelium actively regulates the neuronal ionic and nutrient microenvironment. Although the extent and importance of blood-brain barrier abnormalities in aging and Alzheimer's disease are controversial, considerable evidence exists for a dysfunctional blood-brain barrier. It is our hypothesis that abnormalities in microvascular receptor-mediated signaling pathways may contribute to an altered blood-brain barrier responsiveness in Alzheimer's disease. Abnormalities of the BBB may be age- and/or Alzheimer's disease disease- related. Consequently, microvascular responsiveness in Alzheimer's disease in age-matched, non-demented elderly patientsand i adult control patients will be assessed. In addition, experiments in young and aged rodents are necessary an an immediate and ready source of material on which methods, storage, and age-related changes can be evaluated. Specifically, microvessel adrenergic and cholinergic receptors, adenylate cyclase, and protein kinase C, under both basal and agonist stimulated conditions, will be assessed from the above groups in order to identify- age and disease-related alterations. Experiments are planned to analyze, (1) receptor binding parameters using radioligand binding techniques, receptor-linked Gs function via reconstitution in S49 cyc (G protein deficient) cells, and levels of Gs and Gi using toxin ribosylation; (2) adenylate cyclase levels by measuring cAMP accumulation and [3H]forskolin binding, specificity and activity of this enzyme by phosphoprotein analysis, and mRNA expression by RNA blot analysis; and (3) protein kinase C activity, basal distribution and agonist-stimulated translocation, isoform levels by Western blots, and message levels by Northern analysis. The results will define the function and regulation of intracellular signalling pathways at the blood-brain barrier and may provide a basis for the development of rational therapeutic strategies for improved cerebrovascular and neuronal function in Alzheimer's disease.