Mechanisms of age-related tauopathy

年龄相关 tau 蛋白病的机制

• 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
• 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' s Disease; Alzheimer' 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

 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（由申请人提供）：一大群著名的神经病理学家和神经科学家提出了最近的共识标准，以定义患有这种疾病的新类别的阿尔茨海默氏病（AD）神经病理学变化，现在称为原发性年龄相关性 tau 蛋白病。 PART），在缺乏淀粉样β肽（Aβ）斑块的情况下，PART患者可能会出现AD型神经原纤维缠结（NFT）。 PART 痴呆的患病率尚不清楚，估计范围为 1-7%，但最近的研究发现了一种常见的神经影像和脑脊液生物标志物。约 25% 的非痴呆老年人和 aMCI 患者存在可疑非淀粉样蛋白病理生理学 (SNAP) 特征，这与 PART 显着相似。该应用旨在对 PART 进行集中的组织病理学、分子和严格的遗传学研究，我们的中心假设是 PART 受试者具有构成其 NFT+/Aβ- 表型的独特特征，了解 PART 的分子变化和遗传风险因素。将揭示其发病机制的机制，进而促进我们对颞叶对神经变性的区域脆弱性和 tau蛋白病的总体发病机制的理解。在目标 1 中，我们将验证新的神经病理学标准。 PART 并为阐明疾病负担、发病机制和进展的临床和机制研究奠定基础。这将在目标 2 中使用基于体视学的半定量和定量测量 NFT 负担进行大型痴呆症尸检系列。假设 PART 具有由 AD 型 tau 病理学和非淀粉样蛋白 APP 代谢物组成的分子特征，这将通过使用定量比较有毒 tau 物种和 APP 代谢物的水平和分布来实现。最后，在目标 3 中，我们将检验 PART 具有与 AD 遗传学某些方面重叠的遗传风险特征的假设。例如，MAPT 单倍型），但与其他（例如，APOE 基因型）有所不同，这一目标将通过进行一系列比较频率的关联分析来实现。我们还将使用大量 PART 受试者对 NFT 负担进行全基因组特征分析，以发现新的候选风险等位基因。 tau蛋白病变化具有一系列独特的临床特征、分子变化和遗传风险因素，这项研究具有创新性，因为将 PART 视为一个独立于 Aβ 的过程代表了我们如何从概念上理解 tau蛋白病成分的范式转变。 AD 神经病理改变。