CYTOKINES IN DOWN SYNDROME--LINK TO AD NEUROPATHOLOGY

唐氏综合症中的细胞因子——与 AD 神经病理学的联系

• 批准号: 2769322
• 负责人: PANKAJ D. MEHTA
• 金额: $ 23.42万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769322
• 关键词: Alzheimer's disease; CD4 molecule; CD8 molecule; Downs syndrome; aging; blood chemistry; brain cell; cellular immunity; cerebrospinal fluid; cytokine; enzyme linked immunosorbent assay; gene expression; human subject; immunopathology; immunoregulation; interferon gamma; interleukin 1; interleukin 6; longitudinal human study; messenger RNA; nervous system disorder; neuropsychological tests; polymerase chain reaction; prognosis; tumor necrosis factor alpha

Persons with Down syndrome (DS) (40 years and older), who have come to autopsy show brain lesions similar to those seen in patients with Alzheimer disease (AD). It has also been noted that DS persons have abnormal humoral and cell-mediated immune responses. Little is known regarding the relationship between the immune responses, and the presence of AD neuropathology in DS. However, recent studies have suggested that microglia and inflammatory cytokines participate in the pathogenesis of AD. The overall goal of this project is to increase our understanding of the potential role of the cytokines in the pathogenesis of AD, and its relationship to dementia of the Alzheimer type (DAT) in DS. Preliminary studies of 41 aging persons with DS showed that: 1. interleukin-6 (IL- 6), one of the cytokines with immunoregulatory effects, was significantly increased compared to gender- and age-matched normal controls; and 2. Il- 6 levels were significantly higher in the early stage of DAT compared to those without evidence of DAT. Three hypotheses will be tested: 1. Cytokine abnormalities will precede the appearance of signs of DAT, 2. cytokine abnormalities will be greatest in DA showing the most advanced stages of DAT, and 3. cytokine levels in serum will correlate with those of brain and cerebrospinal fluid (CSF) in DS persons. The goal of the proposed investigation is to examine the levels of IL-6 and related cytokines in blood collected annually over a period of five years to observe sequential and progressive changes. Levels of IL-6, IL-1, tumor necrosis factor alpha, and interferon gamma in serum will be measured from 100 persons with DS (41 years and up), using an ELISA. Similar assays will be performed in sera from equal numbers of gender-and age- matched normal controls to rule out effects of age-associated phenomena in cytokine activation. The data will be correlated with clinical evidence of DAT examined annually using logistical regression analysis methods. The results may lead to the development of a laboratory test to predict early signs of AD before the onset of DAT, and offer a method to monitor changes in the severity of DAT. CSF and serum cytokine levels, and the cellular immune response in blood leukocytes will be examined in a subgroup of DS persons; cytokine messenger RNA expression in DS and control brains will be measured by reverse transcriptase- polymerase chain reaction. The studies will determine the relationship of cytokine production in brain and blood in response to DAT in DS.

唐氏综合症（DS）（40岁及以上）的人 尸检显示与患者相似的脑病变 阿尔茨海默氏病（AD）。 还注意到DS人员有 异常的体液和细胞介导的免疫反应。 鲜为人知 关于免疫反应与存在之间的关系 DS中的AD神经病理学。 但是，最近的研究表明 小胶质细胞和炎性细胞因子参与 广告。 该项目的总体目标是增加我们的理解 细胞因子在AD发病机理中的潜在作用及其 DS中与阿尔茨海默氏症类型（DAT）的痴呆症的关系。 初步的 对41名DS老龄化患者的研究表明：1。白介素-6（il- 6）是具有免疫调节作用的细胞因子之一，显着 与性别匹配和年龄匹配的正常对照相比增加；和2。IL- 与DAT早期相比，6个水平明显更高 那些没有DAT的证据。 将测试三个假设：1。 细胞因子异常将在DAT迹象的出现之前，2。 细胞因子异常将是最先进的DA中最大的 DAT的阶段和3。血清中的细胞因子水平将与这些水平相关 DS人员中的大脑和脑脊液（CSF）。 目标的目标 拟议的研究是检查IL-6和相关的水平 每年在五年内收集血液中的细胞因子 观察顺序和渐进的变化。 IL-6，IL-1，肿瘤的水平 将测量血清中坏死因子α和干扰素γ 使用ELISA的100人（41年及以上）。 相似的 测定将在同等数量的性别和年龄数量的血清中进行 匹配的正常对照以排除与年龄相关现象的影响 在细胞因子激活中。 数据将与临床相关 使用后勤回归分析每年检查DAT的证据 方法。 结果可能会导致实验室测试的发展 在DAT发作之前预测AD的早期迹象，并提供一种方法 监视DAT严重程度的更改。 CSF和血清细胞因子 水平，血清细胞中的细胞免疫反应将是 在DS人员的子组中进行了检查；细胞因子信使RNA表达 在DS和控制大脑中，将通过逆转录酶来衡量 聚合酶链反应。 研究将确定关系 DS中的DAT响应脑和血液中细胞因子的产生。

项目成果

Generation of Rabbit Monoclonal Antibody to Amyloid-β38 (Aβ38): Increased Plasma Aβ38 Levels in Down Syndrome.

兔单克隆抗体淀粉样β38 (Aβ38) 的产生：唐氏综合症血浆Aβ38 水平增加。

• DOI: 10.3233/jad-142592
• 发表时间: 2015
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Mehta,PankajD;Patrick,BruceA;Barshatzky,Marc;Mehta,SangitaP;Frackowiak,Janusz;Mazur-Kolecka,Bozena;Miller,DavidL
• 通讯作者: Miller,DavidL

Alpha2 macroglobulin elevation without an acute phase response in depressed adults with Down's syndrome: implications.

患有唐氏综合症的抑郁成人患者中没有急性期反应的 Alpha2 巨球蛋白升高：影响。

• DOI: 10.1046/j.1365-2788.2000.00287.x
• 发表时间: 2000
• 期刊: Journal of intellectual disability research : JIDR.
• 作者: Tsiouris,JA;Mehta,PD;Patti,PJ;Madrid,RE;Raguthu,S;Barshatzky,MR;Cohen,IL;Sersen,E
• 通讯作者: Sersen,E