Resistance and Vulnerability for Alzheimer's and Related Pathologies

阿尔茨海默病及相关病理的抵抗力和脆弱性

• 批准号: 9897707
• 负责人: Corey T McMillan
• 金额: $ 79.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897707
• 关键词: Address; Admixture; Adult; Age; Age-Years; Aging; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antibodies; Autopsy; Biological; Biological Aging; Biological Markers; Birth; Brain; Brain region; Categories; Chronology; Coin; Cyclin-Dependent Kinase Inhibitor 2A; DNA; DNA Methylation; DNA-Binding Proteins; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Elderly; Epigenetic Process; Exhibits; Frequencies; Funding; Gene Frequency; Genetic; Genetic Transcription; Genotype; Goals; Heterogeneity; Histology; Individual; Investigation; Length; Longevity; Measurement; Measures; Messenger RNA; Molecular; Multivariate Analysis; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Population; Research; Resistance; Resources; Risk; Risk Factors; Sampling; Senile Plaques; Series; Severities; Single Nucleotide Polymorphism; Source; Spatial Distribution; Susceptibility Gene; Tars; Tauopathies; Testing; United States National Institutes of Health; abeta accumulation; age related; aging population; alpha synuclein; brain tissue; digital; frontotemporal lobar dementia-amyotrophic lateral sclerosis; genetic risk factor; genome wide association study; individual variation; molecular pathology; neuropathology; novel; prevent; resistance mechanism; tau Proteins; tau aggregation; telomere; tool; trait

Project Summary/Abstract Detailed neuropathological investigations suggest that nearly all adults >50 years of age have pathological evidence of neurofibrillary tau tangles (NFTs) and rarely (<1%) are lacking any form of molecular pathology. As individuals age there is also an increased risk of NFTs co-occurring with amyloid-beta plaques (Aβ) consistent with Alzheimer's disease (AD) molecular pathology. However, the recently coined term primary age-related tauopathy (PART) describes the presence of NFTs in a subset of older adults in an identical distribution to AD but with absent-to-minimal Aβ pathology. In contrast, there is increasing evidence that AD neuropathology can additionally be accompanied by alpha-synuclein (ASYN), the hallmark of Parkinson's disease (PD), and/or tar- DNA binding protein (TDP-43), the hallmark molecular basis of frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To date, the mechanisms underlying the age-related neuropathological spectrum of NFTs-only in PART and inclusions of ASYN and TDP-43 pathology in AD are unclear. In this proposal we introduce the “resistance hypothesis” that suggests that some individuals have neuro-protective resources that limit their accumulation of Aβ in PART and their accumulation of ASYN and/or TDP-43 pathology in AD. We also consider the co-occurrence of molecular pathologies in related disorders, including ALS and PD. The overarching goal of this proposal is to test the hypothesis that genetic and biological aging mechanisms provide resistance to age-related molecular pathologies and to uncover mechanisms supporting resistance in this aging population. To achieve this goal we will analyze neuropathological and genetic data in >1160 well-characterized autopsy-confirmed samples from our NIA-funded Alzheimer's Disease Center (ADC) and related neuropathology cores, as we as supplement these analyses with similar public datasets. We propose 3 specific aims: (1) Determine whether resistance to age-related molecular pathology is associated with reduced severity and admixture of pathologies; (2) Investigate whether “protective” alleles of single nucleotide polymorphisms associate with resistance against molecular pathology; (3) Evaluate whether efficient “biological” aging of regional brain tissue is protective against molecular pathology, including a DNA measure of single telomere length analysis (STELA), a transcriptional measure of p16 cyclin-dependent kinase inhibitor expression, and an epigenetic measure of DNA methylation (mDNA). Together, by investigating mechanisms of resistance to molecular pathology in aging, this proposal addresses a NIH priority to better understand the common mechanisms and interactions among neurodegenerative diseases. By better understanding the genetic factors that contribute to resistance of molecular pathology we aim to identify candidate pathways for treatment approaches to prevent accumulation of proteinopathies. A significant proportion of the aging neurodegenerative disease population has mixed pathology and this research will provide a template for developing treatment approaches that address this important issue of heterogeneity.

项目摘要/摘要 详细的神经病理学研究表明，几乎所有成年人> 50岁都有病理 神经原纤维tau缠结（NFT）和很少（<1％）的证据缺乏任何形式的分子病理学。作为 个体年龄也增加了与淀粉样蛋白斑块（Aβ）一致的NFT的风险增加 患阿尔茨海默氏病（AD）分子病理学。但是，最近创造的术语初级年龄有关 tauopathy（部分）描述了与AD相同分布的老年人子集中NFT的存在 但是没有到最小的Aβ病理学。相反，有越来越多的证据表明AD神经病理可以 此外，还伴随着帕金森氏病（PD）的标志和/或tar-伴随Alpha-synclein（Asyn）（Asyn） DNA结合蛋白（TDP-43），额颞变性（FTLD）的标志性分子基础和 肌萎缩性侧索硬化症（ALS）。迄今为止，与年龄有关的神经病理学的机制 AD中ASYN和TDP-43病理学的一部分和夹杂物的部分尚不清楚。在这个 提案我们介绍了“抵抗假设”，表明某些人具有神经保护 限制其积累Aβ的资源以及ASYN和/或TDP-43的积累 广告中的病理学。我们还考虑了相关疾病中分子病理的共同发生，包括 ALS和PD。该提案的总体目标是检验遗传和生物衰老的假设 机制提供了对年龄相关的分子病理的抗性，并发现了支持的机制 这个老龄化人口的抵抗。为了实现此目标，我们将分析神经病理学和遗传数据 > 1160个来自我们NIA资助的阿尔茨海默氏病中心（ADC）的尸检验证良好确认的样品 和相关的神经病理学核心，因为我们用类似的公共数据集补充了这些分析。我们 提案3特定目的：（1）确定对年龄相关的分子病理的抗性是否相关 严重程度降低和病理混合； （2）调查是否“保护性”单位等位基因 核苷酸多态性与对分子病理的抗性相关； （3）评估是否 有效的区域脑组织的“生物学”衰老受到保护免受分子病理的保护，包括DNA 单端粒长度分析（Stela）的度量，p16细胞周期蛋白依赖性激酶的转录测量 抑制剂的表达和DNA甲基化（MDNA）的表观遗传测量。一起调查 衰老中对分子病理抗性的机制，该提案旨在解决NIH的优先级以更好 了解神经退行性疾病之间的常见机制和相互作用。好的 了解有助于分子病理抗性的遗传因素，我们旨在识别 治疗方法的候选途径，以防止蛋白质病的积累。重要的 衰老的神经退行性疾病人群的比例患有不同的病理，这项研究将 为开发治疗方法提供了一个模板，以解决这一重要的异质性问题。