Farhadieh Mohammad-Erfan, Ghaedi Kamran
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran.
Front Mol Neurosci. 2023 Sep 20;16:1237874. doi: 10.3389/fnmol.2023.1237874. eCollection 2023.
Alzheimer's disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain's cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including in astrocytes and excitatory neurons, in astrocytes and endothelial cells, and in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor . In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes.
阿尔茨海默病（AD）是一种无法有效治愈的神经退行性疾病，它侵袭大脑细胞，导致记忆丧失以及行为和语言技能的改变。可变剪接是一个受特定细胞类型高度调控的过程，并且与神经退行性疾病等与年龄相关的疾病有关。在死后脑组织的细胞水平上全面检测可变剪接事件（ASEs）可为AD病理学提供有价值的见解。在此，我们通过在一项按细胞类型分类的批量RNA测序研究以及两项来自前额叶皮质的单细胞RNA测序研究中采用生物信息学流程，提供了死后脑组织中的细胞水平ASEs。这项全面分析揭示了AD患者大脑中先前被忽视的剪接和表达变化。在观察到的变化中，与伴侣蛋白相关的转录本的剪接和表达发生了改变，包括在星形胶质细胞和兴奋性神经元中、在星形胶质细胞和内皮细胞中以及在小胶质细胞和受tau病变影响的神经元中，这些变化与剪接因子的差异表达有关。此外，新的未知转录本发生了改变，并且在神经元中的长链非编码RNA等中观察到了结构变化。这项工作提供了一种在神经退行性变中在细胞水平上识别显著ASEs的新策略，该策略揭示了AD中细胞类型特异性的剪接变化。这一发现可能有助于解释剪接与神经退行性疾病结果之间的关联。
