Mechanisms of age-related tauopathy

年龄相关 tau 蛋白病的机制

基本信息

批准号：
9754264
负责人：
John Fonda Crary
金额：
$ 36.94万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754264
关键词：
Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Autopsy Biochemical Biological Markers Brain Categories Cerebrospinal Fluid Characteristics Clinical Cognition Confocal Microscopy Consensus Data Dementia Diagnosis Disease Elderly Enzyme-Linked Immunosorbent Assay Event Frequencies Frontotemporal Lobar Degenerations Functional disorder Genetic Diseases Genetic Risk Genetic study Genotype Goals Haplotypes High Prevalence Immunofluorescence Immunologic Immunohistochemistry Impaired cognition Individual Knowledge Laboratories Lead Measurement Medial Metabolism Modification Molecular Molecular Genetics Molecular Profiling Morphology Nerve Degeneration Neurofibrillary Tangles Pathogenesis Pathogenicity Pathologic Pathology Patients Phenotype Prevalence Process Protein Isoforms Public Health Research Research Personnel Resistance Scientist Series Study Subject Tauopathies Temporal Lobe Testing age related amnestic mild cognitive impairment apolipoprotein E-4 base brain tissue burden of illness case control cerebral amyloidosis cohort disorder control genetic analysis genetic risk factor genome-wide individual patient innovation insight mind control neuroimaging non-demented novel diagnostics novel therapeutic intervention public health relevance risk variant tau Proteins trait ward

项目摘要

DESCRIPTION (provided by applicant): Recent consensus criteria have been put forth by a large group of prominent neuropathologists and neuroscientists to define a new category of Alzheimer's disease (AD) neuropathologic changes. Individuals with this disorder, now termed primary age-related tauopathy (PART), develop AD-type neurofibrillary tangles (NFT) in the absence of amyloid beta peptide (Aβ) containing-plaques. Patients with PART may have normal cognition, amnestic mild cognitive impairment (aMCI), or an amnestic dementia. The prevalence of PART dementia is unclear, with estimates ranging from 1-7%, but PART is likely more pervasive. Recent studies have found a common neuroimaging and cerebrospinal fluid biomarker profile, termed suspected non-amyloid pathophysiol- ogy (SNAP), in ~25% of non-demented elderly individuals and patients with aMCI which shows remarkable similarities to PART. The objective of this application is to perform a focused histopathological, molecular and rigorous genetic study of PART. Our central hypothesis is that subjects with PART have distinct characteristics that underlie their NFT+/Aβ- phenotype. Understanding the molecular changes of, and genetic risk factors for, PART will reveal mechanistic insights into its pathogenesis and in turn advance our understanding of the re- gional vulnerability of the temporal lobe to neurodegeneration and the pathogenesis of tauopathies in general. In aim 1, we will validate the new neuropathologic criteria for PART and lay the groundwork for clinical and mechanistic studies that will elucidate disease burden, pathogenesis and progression. This will be performed in a large dementia autopsy series using stereology-based semiquantitative and quantitative measurements of NFT burden. In aim 2, we will test the hypothesis that PART has a molecular signature consisting of AD-type tau pathology alongside non-amyloidogenic APP metabolites. This will be accomplished by comparing the levels and distribution of toxic tau species and APP metabolites using quantitative immunoblot, ELISA, brightfield immunohistochemistry and immunofluorescence confocal microscopy in autopsy brain tissue from PART, AD, and control cases. Finally, in aim 3 we will test the hypothesis that PART has a genetic risk profile that over laps with some aspects of AD genetics (e.g., MAPT haplotypes) but diverges with respect to others (e.g., APOE genotype). This aim will be accomplished by performing a series of association analyses comparing the frequency of known AD risk alleles in PART, AD and controls. We will also perform a genome-wide quantitative trait analysis of NFT burden using a large cohort of PART subjects to discover new candidate risk alleles. This project will establish that a group of individuals with AD tauopathic changes have a distinct constellation of clinical features, molecular changes and genetic risk factors. The proposed research is innovative because considering PART as an Aβ-independent process represents a paradigm shift in terms of how we conceptual- ize the tauopathic component of AD neuropathologic changes.

描述（由适用提供）：一大批著名的神经病理学家和神经科学家已经提出了最近的共识标准，以定义阿尔茨海默氏病（AD）神经病理学变化的新类别。在没有淀粉样蛋白β胡椒（Aβ）的情况下，这种疾病的个体现在称为年龄与年龄相关的陶氏病（部分），形成AD型神经原纤维缠结（NFT）。患有部分的患者可能具有正常的认知，最宽松的轻度认知障碍（AMCI）或炎症性痴呆症。部分痴呆症的患病率尚不清楚，估计范围为1-7％，但部分可能更普遍。最近的研究发现，在约25％的非痴呆的老年人和患有AMCI的患者中，可疑的无淀粉样病理生产（SNAP）的常见神经影像学和脑脊液生物标志物谱图，其表现出与部分相似的相似之处。该应用的目的是对部分进行集中的组织病理学，分子和严格的遗传研究。我们的核心假设是，具有部分的受试者具有不同特征，这些特征是其NFT+/Aβ-表型的基础。了解部分的分子变化和遗传危险因素的分子变化将揭示机械洞察力的发病机理，从而促进我们对临时叶的重新脆弱性对神经变性的重新脆弱性的理解以及一般而言的金刚病的发病机理。在AIM 1中，我们将验证新的神经病理学标准，以奠定临床和机械研究的基础，以阐明伯恩，发病机理和进展。这将在大型痴呆型尸检系列中使用基于立体的NFT Burnen的半定量和定量测量。在AIM 2中，我们将检验以下假设：部分具有分子特征，该分子特征由AD型Tau病理学以及非淀粉样蛋白异生APP代谢产物组成。这将通过使用定量免疫印迹，ELISA，Brightfield免疫组织化学和免疫荧光共聚焦显微镜在尸检中，从部分，AD和对照病例比较有毒Tau物种和APP代谢产物的水平和分布。最后，在AIM 3中，我们将检验以下假设：部分具有遗传风险特征，该遗传风险特征与AD遗传学的某些方面（例如MAPT单倍型）的某些方面相对于其他遗传学（例如APOE基因型）而有所不同。通过进行一系列关联分析来比较已知的AD风险等位基因的频率，AD和对照组的频率来实现此目标。我们还将使用大量的零件组对NFT燃烧进行全基因组的定量性状分析，以发现新的候选风险等位基因。该项目将确定一群具有a型呼吸病变的个体具有临床特征，分子变化和遗传危险因素的独特星座。拟议的研究具有创新性，因为将部分视为与Aβ无关的过程代表了我们如何概念上的范式转移 - 构成了AD神经病理学变化的tauopathic成分。