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

炎症和 NGF 功能障碍在唐氏综合症阿尔茨海默病病理学演变中的作用

基本信息

批准号：
10250064
负责人：
JORGE A BUSCIGLIO
金额：
$ 56.37万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250064
关键词：
Adolescent Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Appearance Autopsy Biochemical Biological Biological Markers Body Fluids Brain California Canada Cell Culture Techniques Cells Chromosome 21 Clinical Cognitive Cognitive deficits Complement Data Dementia Deposition Diagnostic Disease Disease Progression Down Syndrome Elderly Evolution Functional disorder Genes Genetic Diseases Genetic Models Goals Hospitals Human Human Chromosomes Impaired cognition In Vitro Individual Infant Inflammation Inflammatory Investigation Link Liquid substance Live Birth Longevity Measures Metabolic Pathway Metabolic dysfunction Metabolism Molecular Molecular Genetics Nerve Growth Factors Neurofibrillary Tangles New York Pathogenesis Pathology Pathway interactions Patients Penetrance Peptides Phase Plasma Population Process Proteomics Quantitative Reverse Transcriptase PCR Regulation Risk Role Sampling Senile Plaques Signal Transduction Spain Study models System Testing Tissues Transcript Trisomy Universities Western Blotting abeta accumulation asymptomatic Alzheimer’s disease basal forebrain base biomarker discovery cholinergic clinically relevant cohort developmental genetics early detection biomarkers extracellular fetal high risk inflammatory marker multidisciplinary neonate neuroinflammation new therapeutic target novel potential biomarker pre-clinical tau Proteins tau-1 tool

项目摘要

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.

项目摘要/摘要患有阿尔茨海默氏病风险的人（AD）经历了较长的，无症状的疾病阶段在没有外观的情况下，以病理的成绩积累为特征的进展认知赤字。唐氏综合症（DS）患者代表了一个人口，众多人群的广告风险很高 AD病理学在大多数DS受试者中的渗透，使DS成为出色的自然遗传模型为了研究AD的神经病理学机制和鉴定潜在的AD生物标志物。鉴于可靠的早期诊断工具的当前局限性，生物标志物的发现表明了包括患有DS的患者的个体中的阿尔茨海默氏病病理学是最大的临床相关性。当前提案的总体目标是调查新颖的，未表征的生物标志物 DS中最早的AD临床前阶段。为了实现这一目标，协作努力将整合来自验尸后脑研究，原发性人类细胞培养研究和生物液（血浆和CSF）研究在大型的DS和匹配的对照对象中。该提案的中心假设是细胞内淀粉样β的早期积累 DS大脑中的肽（Aβ）将诱导NGF代谢功能障碍进行的中枢神经系统注射在细胞外淀粉样菌斑沉积之前。此外，中枢神经系统的NGF妥协在AD病理的“初步”阶段，应在DS体液中检测到代谢表现出明显的痴呆症。为了检验既定假设，将实现三个具体目标：目标1：探索在DS中，CNS促炎过程和NGF功能障碍的发生。使用验尸DS大脑在不同年龄，DS中的感染和NGF功能障碍的出现将是研究以暂时重建AD发病机理的演变。目标2：研究分子使用神经炎症和NGF代谢功能障碍将DS早期AD病理学的机制联系起来胎儿人类原发性皮质培养物。这些研究将完成目标1和3，并将阐明分子早期AD发病机理的途径。目标3：分析Aβ，TAU，NGF相关的表达和来自整个生命周期的DS受试者的匹配的血浆和CSF样品中的炎症标记。这些研究将测试AIMS -1和-2中研究的标记是否反映在匹配的血浆和CSF中来自DS与对照对象的样本。该多学科的多学科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，它将有助于预测的发作和轨迹失智。此外，计划的研究可能会导致两者中新型治疗靶标的鉴定 DS个人和零星的广告群。