Resistance and Vulnerability for Alzheimer's and Related Pathologies

项目摘要/摘要 详细的神经病理检查表明，几乎所有50岁的成年人都有病理性。 神经原纤维tau缠结(NFTs)的证据很少(1%)缺乏任何形式的分子病理。AS 年龄越大，NFTs与淀粉样β蛋白斑块(A-β)并存的风险也会增加 阿尔茨海默病(AD)分子病理学。然而，最近创造的术语初级年龄相关 肌萎缩侧索硬化症(部分)描述了一组老年人中NFT的存在，其分布与AD相同 但有从缺失到最小的A-β病理。相比之下，越来越多的证据表明，阿尔茨海默病的神经病理可以 此外还伴有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)，额颞部退行性变(FTLD)的标志性分子基础和 肌萎缩侧索硬化症(ALS)。到目前为止，年龄相关神经病理的潜在机制 AD中仅有部分NFTs的频谱以及ASYN和TDP-43病理的包涵体尚不清楚。在这 建议我们引入“抵抗力假说”，即某些个体具有神经保护作用。 限制β部分积累和ASYN和/或TDP-43积累的资源 AD中的病理学。我们还考虑了相关疾病中分子病理学的共同出现，包括 肌萎缩侧索硬化症和警局。这项提议的首要目标是检验这样一种假设，即遗传和生物衰老 机制提供了对年龄相关分子病理的抵抗力，并揭示了支持 在老龄化的人口中的抵抗力。为了实现这一目标，我们将分析神经病理和遗传数据 来自NIA资助的阿尔茨海默病中心(ADC)的1160个特征良好的尸检确认样本 以及相关的神经病理学核心，作为对这些分析的补充，我们使用类似的公共数据集。我们 提出3个具体目标：(1)确定与年龄相关的分子病理抵抗是否相关 减少严重程度和混合病理；(2)调查单一的保护性等位基因 核苷酸多态与对分子病理的耐药性相关；(3)评估 有效的“生物”老化的局部脑组织是保护免受分子病理，包括DNA 单个端粒长度分析(STELA)是p16细胞周期蛋白依赖性激酶的转录指标 抑制物的表达，以及DNA甲基化的表观遗传措施(MDNA)。一起，通过调查 衰老中抵抗分子病理的机制，这项建议解决了NIH的优先事项，以更好地 了解神经退行性疾病之间的共同机制和相互作用。变得更好 了解导致分子病理学抗性的遗传因素，我们的目标是确定 预防蛋白质病堆积的治疗方法的候选路径。一个重要的 老年神经退行性疾病人群中有混合病理的比例，这项研究将 为开发治疗方法提供模板，以解决这一重要的异质性问题。

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.