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) 患者（40 岁及以上） 尸检显示脑部病变与患有以下疾病的患者相似 阿尔茨海默病（AD）。 还注意到 DS 人员 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。 然而，最近的研究表明 小胶质细胞和炎症细胞因子参与了发病机制 广告。 该项目的总体目标是增加我们的理解 细胞因子在 AD 发病机制中的潜在作用及其 与 DS 中阿尔茨海默型痴呆 (DAT) 的关系。 初步的 对 41 名老年 DS 患者的研究表明： 1. 白细胞介素 6 (IL-6) 6）具有免疫调节作用的细胞因子之一，具有显着的免疫调节作用。 与性别和年龄匹配的正常对照相比有所增加； 2. 伊尔- 6 水平在 DAT 早期显着高于 那些没有 DAT 证据的人。 将检验三个假设：1. 细胞因子异常会先于 DAT 体征出现，2。 细胞因子异常在 DA 中最为严重，显示出最先进的状态 DAT 的阶段，以及 3. 血清中的细胞因子水平将与这些相关 DS 患者的大脑和脑脊液 (CSF) 的变化。 的目标 拟议的调查是检查 IL-6 和相关的水平 五年内每年收集血液中的细胞因子 观察顺序和渐进的变化。 IL-6、IL-1、肿瘤水平 将测量血清中的坏死因子α和干扰素γ 使用 ELISA，从 100 名 DS 患者（41 岁及以上）中获得。 相似的 检测将在相同数量的性别和年龄的血清中进行 匹配正常对照以排除与年龄相关的现象的影响 在细胞因子激活中。 数据将与临床相关 每年使用逻辑回归分析检查 DAT 的证据 方法。 结果可能会导致实验室测试的发展 在 DAT 出现之前预测 AD 的早期症状，并提供一种方法 监测 DAT 严重程度的变化。 脑脊液和血清细胞因子 水平，血液白细胞的细胞免疫反应将 在 DS 人员分组中进行检查；细胞因子信使RNA表达 DS 和对照大脑中的细胞将通过逆转录酶进行测量 聚合酶链式反应。 研究将确定关系 DS 中 DAT 对大脑和血液中细胞因子产生的反应。

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