Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

总结 阿尔茨海默病（Alzheimer's disease，AD）的发病机制与年龄密切相关，患病率呈上升趋势 在60岁以后呈指数增长。在70岁左右的人中，有5%的人受到影响， 85岁以上的老年人中有三分之一患有AD。除了在患有癌症的患者中看到的急剧增加外， 在工业化国家，与年龄相关的神经退行性疾病， 在发展中国家，也观察到与人口老龄化同时发生的变化。目前没有 可以减缓、停止或逆转疾病进展的AD治疗方法。这一日益严重 只有我们能够更全面地了解AD的发病机制， 这显然需要对人类生物衰老有深入的了解。该项目由博士提出。 盖奇和他的同事们将首次在人类模型中挑战细胞衰老的重要性， 这种疾病盖奇实验室最近表明，直接将人成纤维细胞转化为诱导的 神经元（iN）保留了细胞衰老的特征，允许检测与 人类衰老相比之下，诱导多能干细胞（iPSC）重编程会消除年龄依赖性 因此，iPSC衍生的神经元类似于再生的细胞。为了更好地了解 神经元细胞衰老对散发性AD病理学的影响，该组的第一个目的是产生 来自大量临床特征良好的AD患者的表型老化和再生神经元， 匹配的控制。根据无偏转录组方法，他们将分析AD特异性基因 表达谱，并努力了解哪些AD特异性基因表达特征和 相关的机制是年龄依赖性的，并且是年龄无关的。 目前正在出现核质转运和输入受体RanBP 17的失调 作为衰老和神经退行性疾病研究的主要课题。在他们的第二个目标中，盖奇博士的团队将 工作，以确定尚未充分研究的蛋白质RanBP 17的结合伙伴和确切的功能。中 第三个目标，他们将利用他们最近建立的报告系统来测量核， 年轻和老年AD神经元胞质区室化和基于核转运探针 使用活细胞成像方法的年龄依赖性AD病理学的介质。 DNA损伤的依赖性累积有助于我们细胞中的遗传多样性， 这一过程被称为体细胞镶嵌。最近的证据表明，AD只需要一个小种子 病理学可由此扩散到整个大脑，躯体嵌合体可能起重要作用 在偶发性AD的发展过程中。在第四个目标中，盖奇团队将使用同步DNA和RNA 对来自同一患者的单个死后神经元和iN进行测序，并询问DNA 拷贝数的变化可以将神经元转变为潜在的“AD种子”细胞。

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.