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

项目总结/摘要 有患阿尔茨海默病风险的个体经历了一个漫长的、无症状的疾病阶段 进展，其特征是在没有明显的 认知缺陷唐氏综合征（DS）患者代表AD高风险人群， 在大多数DS受试者中发现AD病理学的异常，使DS成为一种杰出的自然遗传模型 用于研究AD的神经病理学机制和用于鉴定潜在的AD生物标志物。鉴于 目前可靠的早期诊断工具的局限性，生物标志物的发现， 高危个体（包括DS患者）的阿尔茨海默病病理学具有极高的临床相关性。 当前提案的总体目标是研究新的，未表征的生物标志物， DS中AD的最早临床前阶段。为了实现这一目标，将通过协作努力整合来自 死后脑研究、原代人细胞培养研究和生物体液（血浆和CSF）研究 在DS和匹配对照受试者的大型充分表征队列中。 该提案的中心假设是，细胞内淀粉样β蛋白的早期积累 DS脑内Aβ肽可诱导中枢神经系统炎症反应，并伴有神经生长因子代谢障碍 在细胞外淀粉样斑块沉积之前。此外，神经生长因子的中枢神经系统损害 应在AD病理学的“初期”阶段，在 表现出明显的痴呆 为了检验所述假设，将实现三个具体目标：目标1：探索 在DS的整个生命周期中发生CNS促炎过程和NGF功能障碍。使用 在不同年龄的死后DS脑中，DS中炎症和NGF功能障碍的出现将是 研究以在时间上重建AD发病机制的演变。目的2：研究分子生物学 将DS的早期AD病理学与神经炎症和NGF代谢功能障碍联系起来的机制， 人胎原代皮层培养物。这些研究将补充目标1和目标3，并将阐明分子生物学的 早期AD发病机制的潜在途径。目的3：分析Aβ、tau蛋白、神经生长因子相关蛋白及神经胶质瘤的表达， 在整个生命周期内，DS受试者的匹配血浆和CSF样本中的炎症标志物。这些 研究将测试目标-1和2中研究的标志物是否反映在匹配的血浆和CSF中 DS与对照受试者的样本。 这个多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，并将有助于预测 痴呆此外，计划中的研究可能会导致在这两种疾病中发现新的治疗靶点。 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.