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.

项目总结/摘要 详细的神经病理学研究表明，几乎所有>50岁的成年人都有病理性的 神经元性tau缠结（NFT）的证据，并且很少（<1%）缺乏任何形式的分子病理学。作为 在老年人中，NFT与淀粉样β斑块（Aβ）共同发生的风险也增加， 阿尔茨海默病（AD）的分子病理学。然而，最近创造的术语“与年龄有关的初级 tau蛋白病（PART）描述了NFT在老年人亚组中的存在，其分布与AD相同 但没有或只有轻微的Aβ病变相反，越来越多的证据表明，AD神经病理学可以 此外还伴随有α-突触核蛋白（ASYN），帕金森病（PD）的标志，和/或焦油， DNA结合蛋白（TDP-43）是额颞叶变性（FTLD）的标志性分子基础， 肌萎缩侧索硬化症（ALS）。到目前为止，年龄相关的神经病理学的潜在机制 PART中仅NFT的谱以及AD中ASYN和TDP-43病理学的包含尚不清楚。在这 建议我们引入“抵抗假说”，这表明一些人具有神经保护作用， 限制PART中Aβ蓄积和ASYN和/或TDP-43蓄积的资源 AD的病理学我们还考虑了相关疾病中分子病理学的共同发生，包括 ALS和PD。这项提案的首要目标是检验遗传和生物老化的假设， 机制提供对年龄相关的分子病理学的抵抗力，并揭示支持 在这个老龄化的群体中。为了实现这一目标，我们将分析神经病理学和遗传学数据， >1160个来自我们的NIA资助的阿尔茨海默病中心（ADC）的经过尸检确认的样本 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这些分析。我们 提出了3个具体目标：（1）确定是否与年龄相关的分子病理学抵抗有关 （2）研究单个基因的“保护性”等位基因是否具有降低的严重性和混合性; 核苷酸多态性与分子病理学抗性相关;（3）评估是否 局部脑组织的有效“生物”老化可以防止分子病理学，包括DNA 单个端粒长度分析（STELA）的测量，p16细胞周期蛋白依赖性激酶的转录测量 抑制剂表达和DNA甲基化（mDNA）的表观遗传学测量。通过调查 抗衰老的分子病理学机制，该提案提出了NIH优先考虑更好地 了解神经退行性疾病之间的共同机制和相互作用。通过更好 了解有助于分子病理学耐药性的遗传因素，我们的目标是确定 预防蛋白质病积累的治疗方法的候选途径。显著 老年神经退行性疾病人群的比例具有混合病理学，这项研究将 为开发解决异质性这一重要问题的治疗方法提供了一个模板。