Loss of nuclear integrity is sufficient to induce age-associated changes and Alzheimer's pathology in hPSC-derived cortical neurons.

项目摘要： 阿尔茨海默病(AD)是美国最常见的神经退行性疾病，影响 估计有540万名患者48。到目前为止，还没有有效的治疗方法和有限的治疗方法。 病人49.虽然少数AD病例与淀粉样前体蛋白基因突变有关 在处理过程中，大多数AD病例的遗传基础仍然知之甚少。诱导多能干细胞 (IPSCs)通过提供无限的疾病供应，为研究AD的遗传学提供了一个独特的机会- 同时保留其体细胞供体51的遗传背景。研究表明， IPSC重新编程的过程重置了患者IPSC5的年龄。因此，来自IPSCs的细胞倾向于 产生未成熟和产前细胞类型，这是迟发性疾病建模的主要障碍5，6。 老化方案是加速IPSC来源的细胞衰老的一种新策略，用于晚期建模 退行性疾病表型5，6。虽然这些方案已经建立用于产生基于IPSC的 帕金森氏病的模型，它们还没有被应用于AD。有大量研究表明， 随着年龄的增长和AD患者大脑中发生的核稳态的多个方面的下降，包括 层蛋白的差异表达，核质转运活性的改变，以及 核孔素和转运蛋白8-10、22、24、25、35-38。因此，核完整性的丧失是有可能的 足以在hPSC来源的皮质神经元中诱导与年龄相关的和与AD相关的病理变化。 拟议的研究项目旨在使用遗传策略来模拟年龄相关的变化 确定核扰动是否足以驱动细胞年龄的其他方面并增强AD 病理学。这些研究可以创建一个与年龄有关的创新AD模型，开发新的方法来治疗 对其他细胞类型的迟发性疾病进行建模，并为细胞和核的驱动因素提供新的见解 衰老。

Project Abstract: Alzheimer’s Disease (AD) is the most common neurodegenerative disease in the United States affecting an estimated 5.4 million patients 48. To date, there are no effective cures and limited therapies available for patients 49. While a small number of AD cases are linked to genetic mutations in Amyloid Precursor Protein processing, the genetic basis of most AD cases remains poorly understood 50. Induce Pluripotent Stem Cells (iPSCs) provide a unique opportunity to study the genetics of AD, by providing an unlimited supply of disease- relevant tissue while retaining the genetic background of their somatic cell donor 51. Studies have shown the process of iPSC reprogramming resets the age of patient iPSCs 5. Consequently, cells derived from iPSCs tend to yield immature and prenatal cell types, presenting a major hurdle for late-onset disease modelling 5, 6. Induced aging protocols are a novel strategy for accelerating age in iPSC-derived cells for modelling late-stage degenerative disease phenotypes 5,6. While these protocols have been established for generating iPSC-based models of Parkinson’s Disease, they have yet to be applied to AD. There are numerous studies which describe a decline in multiple aspects of nuclear homeostasis that occur with age and in AD patient brains, including differential expression of lamin proteins, a shift in nuclear-cytoplasmic transport activity, and a decline in nucleoporin and transport proteins 8-10, 22, 24, 25, 35-38. It is therefore plausible that a loss of nuclear integrity is sufficient to induce age-related and pathological changes associated with AD in hPSC-derived cortical neurons. The proposed research project aims to use genetic strategies to mimic age-associated changes within the nucleus to determine if nuclear perturbation is sufficient to drive other aspects of cellular age and potentiate AD pathology. These studies could create an innovative age-implicated model of AD, develop novel methods for modelling late-onset diseases in other cell types, and provide new insights into drivers of cellular and nuclear aging.