Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Translational Mass Spectrometry Research Group, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
J Neurochem. 2021 Oct;159(2):305-317. doi: 10.1111/jnc.15315. Epub 2021 Mar 2.
Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease-associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC-derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post-translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC-derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents.
诱导多能干细胞（iPSC）技术使体外生成人类神经元成为可能，这些神经元包含细胞供体的确切基因组，因此可以从具有相关疾病基因型的个体中生成疾病模型。这种方法已被广泛用于模拟阿尔茨海默病和额颞叶痴呆的遗传性形式。iPSC 衍生的神经元模型与靶向质谱分析相结合，为研究人类神经元生理学和病理学中特定蛋白质的调控提供了前所未有的见解。例如，能够研究 tau 和 APP/Aβ，具体包括：蛋白质同工型表达、切割片段的相对水平、聚集物种和功能关键的翻译后修饰。质谱分析的使用能够确定 iPSC 衍生模型与在人类大脑中观察到的疾病特征的接近程度。这篇综述将重点介绍目前使用 iPSCs 和质谱分析来模拟阿尔茨海默病和痴呆症的研究进展。我们接着表达我们的乐观态度，因为在不久的将来，研究将利用这一先例，结合新的技术，如基因组编辑和稳定同位素标记，为深入了解早期神经退行性过程和开发新的治疗药物提供真正的进展。
