Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞衰老情况

• 批准号: 10153611
• 负责人: FRED H GAGE
• 金额: $ 48.5万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153611
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animal Model; Animals; Attention; Autopsy; Binding; Biological; Biological Aging; Brain; Cell Aging; Cell Nucleus; Cells; Clinical; Color; Copy Number Polymorphism; DNA; DNA Damage; DNA copy number; DNA sequencing; Defect; Dependence; Detection; Developed Countries; Development; Disease; Disease Progression; Disease model; Embryonic Development; FOXO3A gene; Fibroblasts; Fluorescence; Gene Expression; Gene Expression Profile; Genetic; Genetic Variation; Human; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Life; Light; Longevity; Measures; Mediator of activation protein; Modeling; Molecular; Monitor; Mosaicism; Mutate; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Import; Nuclear Pore; Nuclear Pore Complex; Nuclear Translocation; Pathogenesis; Pathologic; Pathology; Patients; Permeability; Phenotype; Play; Population; Prevalence; Process; Proteins; Rejuvenation; Reporter; Research; Resolution; Risk Factors; Role; Sampling; Seeds; Solid; Stimulus; System; Testing; Time; Tissues; Transgenic Mice; Work; age related; age related neurodegeneration; aging brain; base; cellular pathology; cellular targeting; cohort; disorder control; early onset; effective therapy; familial Alzheimer disease; human model; human old age (65+); imaging approach; induced pluripotent stem cell; insight; live cell imaging; middle age; mild cognitive impairment; mutant; normal aging; nucleocytoplasmic transport; overexpression; preservation; receptor; tandem mass spectrometry; transcriptome; transcriptome sequencing; whole genome

SUMMARY Pathogenesis of Alzheimer’s disease ( AD) is highly age-related and prevalence increases exponentially after the age of 60. While at the age of 70 around 5% of all people are affected, more than one third over the age of 85 are afflicted with AD. In addition to the dramatic increase seen in patients suffering from age-related neurodegenerative disorders in industrialized countries, a substantial increase in AD patients in the developing world is also observed in tandem with their aging populations. Currently, there are no treatments available for AD that could slow, halt or reverse the progression of the disease. This growing problem can only be mitigated if we can gain a more complete understanding of AD pathogenesis, which obviously demands a solid understanding of human biological aging. This project proposed by Dr. Gage and colleagues will, for the first time, challenge the importance of cellular aging in a human model for the disease. The Gage lab has recently shown that direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of cell aging, allowing the detection of cellular pathologies relevant to human aging. By contrast, induced pluripotent stem cell (iPSC) reprogramming erases age-dependent differences; iPSC-derived neurons thus resemble rejuvenated cells. To better understand the impact of neuronal cell aging on the pathology of sporadic AD, the first aim of this group is to generate both phenotypically old and rejuvenated neurons from a large set of clinically well-characterized AD patients and matched controls. Following an unbiased transcriptome approach, they will analyze for AD-specific gene expression profiles and work to understand which of the AD-specific gene expression signatures and related mechanisms are age-dependent and which are age-independent. Dysregulation of nucleo-cytoplasmic transport and the import receptor RanBP17 are currently emerging as major topics in aging and neurodegenerative disease research. In their second aim, Dr. Gage's team will work to identify the binding partners and exact functions of the yet understudied protein RanBP17. In a third aim, they will harness their recently established reporter system to measure nucleo- cytoplasmic compartmentalization in young and old AD neurons and probe for nuclear transport-based mediators of age-dependent AD pathology using live cell imaging approaches. Age-dependent accumulation of DNA damage contributes to genetic diversity among our cells, a process known as somatic mosaicism. As recent evidence suggests that AD only needs a small seed from which the pathology can spread throughout the brain, somatic mosaicism might play an important role in the development of sporadic AD. In a fourth aim, the Gage team will use simultaneous DNA and RNA sequencing of single post-mortem neurons and iNs from the same patients and ask to what extent DNA copy number variations can turn a neuron into a potential `AD seed' cell.

概括 阿尔茨海默氏病（AD）的发病机理高度与年龄有关，流行率增加 在60岁以后，成倍地。 85岁以上的第三名患有AD。除了患者的急剧增加 从工业化国家中与年龄相关的神经退行性疾病，AD患者大幅增加 在发展中国家中，还与人口老龄化同时观察到。目前，没有 可用于慢速，停止或扭转疾病进展的AD处理。这个成长 只有在我们可以更完整地了解AD发病机理的情况下，才能缓解问题， 这显然需要对人类生物学衰老有牢固的了解。这个由博士提出的项目 Gage及其同事将首次挑战人类模型中细胞衰老的重要性 疾病。 Gage Lab最近表明，人成纤维细胞直接转化为诱导 神经元（INS）保留细胞衰老的特征，从而发现与细胞病理相关的细胞病理学 人类衰老。相比之下，诱导的多能干细胞（IPSC）重编程消除了年龄的依赖性 差异；因此，IPSC衍生的神经元类似于复兴的细胞。更好地了解 神经元细胞衰老在零星AD的病理上，该组的第一个目的是生成 从表型上旧的，恢复活力的神经元，来自大量临床表征良好的AD患者， 匹配的控件。遵循公正的转录组方法，他们将分析AD特异性基因 表达曲线和工作以了解哪些AD特异性基因表达特征和 相关机制是依赖年龄的，并且是独立的。 目前正在出现核质质运输和进口接收器RANBP17的失调 作为衰老和神经退行性疾病研究的主要主题。在第二个目标中，Gage博士的团队将 努力确定尚未理解的蛋白质RANBP17的结合伙伴和精确功能。在 第三目的，他们将利用他们最近建立的报告基因系统来测量核 - 年轻人和老式AD神经元中的细胞质分区以及基于核转运的探针 使用活细胞成像方法的年龄依赖性AD病理介体。 DNA损伤的年龄依赖性积累有助于我们的细胞之间的遗传多样性， 一个称为躯体镶嵌的过程。由于最近的证据表明，广告只需要一个小种子 病理可以从中传播到整个大脑，体细胞镶嵌可能起重要作用 在第四个目标中，仪表团队将使用简单的DNA和RNA 单个验尸神经元和来自同一患者的INS的测序，并询问DNA在多大程度上 拷贝数变化可以将神经元变成潜在的“ AD种子”细胞。