Lee Christopher, Willerth Stephanie M, Nygaard Haakon B
Graduate Program in Neuroscience, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Graduate Program in Neuroscience, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada; Department of Mechanical Engineering and Division of Medical Sciences, University of Victoria, 3800 Finnerty Road, Victoria, B.C. V8W 2Y2, Canada.
Prog Neurobiol. 2020 Sep;192:101804. doi: 10.1016/j.pneurobio.2020.101804. Epub 2020 May 25.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by a progressive deterioration in multiple facets of cognitive function. As the average age of the population rises, AD poses a massive current and future healthcare threat. Today, there is no cure for AD nor well-established interventions to slow progression, and treatment is largely symptomatic. The failure rate for new drugs in clinical trials has remained high, pointing out a critical need for better disease modeling that can enhance our understanding of basic disease pathophysiology, leading to better drug discovery and preclinical validation. The advent of induced pluripotent stem cells (iPSCs) has allowed researchers access to an unlimited supply of patient cells that can be differentiated into a neural fate, allowing for modeling of neurological disorders such as AD. This development has propelled AD research and presents opportunities to produce more accurate AD models to facilitate research into pathophysiology as well as drug screening and development. In this review, we conduct an in-depth assessment of the literature to identify the majority of work to date on patient-derived iPSCs. We outline research into both the familial and sporadic forms of the disease, as well as modern methods of modeling the disease three-dimensionally. Finally, we identify challenges to be addressed and areas of further research for iPSC modeling of AD.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征是认知功能的多个方面逐渐恶化。随着人口平均年龄的上升，AD对当前和未来的医疗保健构成了巨大威胁。如今，AD既无法治愈，也没有成熟的减缓疾病进展的干预措施，治疗主要是对症治疗。临床试验中新药的失败率一直很高，这表明迫切需要更好的疾病模型，以增强我们对疾病基本病理生理学的理解，从而实现更好的药物发现和临床前验证。诱导多能干细胞（iPSC）的出现使研究人员能够获取无限量的患者细胞，这些细胞可以分化为神经细胞，从而实现对AD等神经疾病的建模。这一进展推动了AD研究，并为生成更准确的AD模型提供了机会，以促进对病理生理学的研究以及药物筛选和开发。在这篇综述中，我们对文献进行了深入评估，以确定迄今为止关于患者来源的iPSC的大部分研究工作。我们概述了对该疾病的家族性和散发性形式的研究，以及三维建模该疾病的现代方法。最后，我们确定了AD的iPSC建模需要解决的挑战和进一步研究的领域。
