The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome

项目摘要/摘要 阿尔茨海默病(AD)的高危人群经历一段漫长的无症状的疾病阶段 进行性疾病，其特征是在缺乏明显症状的情况下病理逐渐积累 认知缺陷。唐氏综合征(DS)患者代表了AD的高危人群，并完全 AD病理在大多数DS受试者中的外显性，使DS成为一种杰出的自然遗传模型 用于研究AD的神经病理机制和识别潜在的AD生物标志物。给定 目前可靠的早期诊断工具的局限性，生物标志物的发现标志着疾病的演变 阿尔茨海默病高危个体的病理学，包括DS患者，具有最大的临床相关性。 目前提案的总体目标是研究新的、未表征的生物标志物 阿尔茨海默病的最早临床前阶段为DS。为了实现这一目标，协作工作将整合来自 死后脑研究、原代人类细胞培养研究和生物体液(血浆和脑脊液)研究 在一大群特征良好的DS和匹配的对照组受试者中。 该提议的中心假设是细胞内淀粉样β蛋白的早期积累 DS脑内多肽(A-β)可诱导中枢炎症并伴有神经生长因子代谢功能障碍 在细胞外淀粉样斑块沉积之前。此外，NGF的中枢神经系统损害 在AD病理的“早期”阶段，应在DS体液中检测到代谢，然后 表现为明显的痴呆。 为了检验所陈述的假设，将实现三个具体目标：目标1：探索 在DS患者的整个生命周期中，中枢神经系统促炎过程和NGF功能障碍的发生。vbl.使用 在不同年龄段的DS尸检脑中，DS患者会出现炎症反应和NGF功能障碍 旨在从时间上重建AD发病机制的演变。目的2：研究分子 阿尔茨海默病早期AD病理与神经炎症和神经生长因子代谢功能障碍 人胎脑皮质原代培养。这些研究将补充目标1和目标3，并将阐明分子 阿尔茨海默病早期发病机制的研究。目的3：分析Aβ、tau、NGF相关基因的表达。 DS患者一生中配对的血浆和脑脊液样本中的炎症标记物。这些 研究将测试AIMS-1和-2中研究的标志物是否反映在匹配的血浆和脑脊液中 DS和对照受试者的样本。 这一多PI多学科的建议将揭示基本的分子病理生物学机制 对于DS中的AD，它将识别生物标志物，并有助于预测AD的发病和轨迹。 痴呆症。此外，计划中的研究可能会导致确定两种药物的新治疗靶点 DS个体和散发性AD人群。

PROJECT SUMMARY/ABSTRACT Individuals at risk of Alzheimer’s disease (AD) undergo a long, asymptomatic phase of disease progression that is characterized by the gradual accumulation of pathology in the absence of apparent cognitive deficit. Down syndrome (DS) patients represent a population at high risk of AD with complete penetrance of AD pathology in the majority of DS subjects, making DS an outstanding natural genetic model for the study of neuropathological mechanisms of AD and for identifying potential AD biomarkers. Given the current limitations in reliable early diagnostic tools, the discovery of biomarkers signalling the evolution of Alzheimer’s disease pathology in individuals at risk, including those with DS, is of utmost clinical relevance. The overall goal of the current proposal is to investigate novel, uncharacterized biomarkers at the earliest preclinical stages of AD in DS. To achieve this goal, a collaborative effort will integrate data from post-mortem brain studies, primary human cell cultures studies, and biological fluids (plasma and CSF) studies in a large well-characterized cohort of DS and matched control subjects. The central hypothesis of the proposal is that the early accumulation of intracellular amyloid beta peptide (Aβ) in DS brains will induce CNS inflammation accompanied by NGF metabolic dysfunction prior to extracellular amyloid plaque deposition. Furthermore, the CNS compromise of NGF metabolism should be detected in DS body fluids at ‘incipient’ stages of the AD pathology, before the presentation of overt dementia. To test the stated hypothesis, three Specific Aims will be accomplished: Aim 1: To explore the occurrence of a CNS pro-inflammatory process and NGF dysfunction throughout the lifespan in DS. Using post-mortem DS brains at different ages, the appearance of inflammation and NGF dysfunction in DS will be investigated to temporally reconstruct the evolution of AD pathogenesis. Aim 2: To investigate molecular mechanisms that link early AD pathology in DS with neuroinflammation and NGF metabolic dysfunction using fetal human primary cortical cultures. These studies will complement Aims 1 and 3 and will elucidate molecular pathways underlying early AD pathogenesis. Aim 3: To analyze the expression of Aβ, tau, NGF-related and inflammatory markers in matched plasma and CSF samples from DS subjects across the lifespan. These studies will test whether markers investigated in Aims- 1 and -2 are reflected in matched plasma and CSF samples from DS versus control subjects. This multi-PI multidisciplinary proposal will reveal fundamental molecular pathobiological mechanisms for AD in DS, it will identify biomarkers, and it will assist in the prediction of the onset and trajectory of dementia. In addition, the planned studies will likely lead to the identification of novel therapeutic targets in both DS individuals and sporadic AD populations.