Department of Neurology, The First Hospital of Changsha, Changsha, Hunan Province, China.
Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
Aging (Albany NY). 2021 Oct 27;13(21):24086-24100. doi: 10.18632/aging.203652.
Alzheimer's disease, the most common form of dementia in the elderly, is a kind of neurodegenerative disease. However, its pathogenesis and diagnosis remain unclear. M6A is related to nervous system development and neurodegenerative diseases. Here in this study, using multiple RNA-seq datasets of Alzheimer's brain tissues, along with bioinformatic analysis, we innovatively found that m6A reader protein IGF2BP2 was abnormally highly expressed in Alzheimer's patients. After compared between Alzheimer's and normal brain samples, and between IGF2BP2- high and IGF2BP2- low subgroups of Alzheimer's patients, we took the shared differentially expressed genes as the relevant gene sets of IGF2PB2 affecting Alzheimer's disease occurrence for subsequent analysis. Then, weight gene correlation analysis was conducted and 17 functional modules were identified. The module that most positively correlated with Alzheimer's disease and IGF2PB2-high subgroups were mainly participated in ECM receptor interaction, focal adhesion, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. Afterwards, a hub gene-based model including 20 genes was constructed by LASSO regression and validated by ROC curve for Alzheimer diagnosis. Finally, we preliminarily elucidated that IGF2BP2 could bind with mRNAs in a m6A-dependent manner. This study first elucidates the pathogenic role of IGF2BP2 in Alzheimer's disease. IGF2BP2 and its relevant m6A modifications are potential to be new diagnostic and therapeutic targets for Alzheimer's patients.
阿尔茨海默病是老年人最常见的痴呆症类型，属于一种神经退行性疾病。然而，其发病机制和诊断仍然不清楚。m6A 与神经系统发育和神经退行性疾病有关。在本研究中，我们创新性地使用了多个阿尔茨海默病脑组织的 RNA-seq 数据集，并结合生物信息学分析，发现 m6A 阅读蛋白 IGF2BP2 在阿尔茨海默病患者中异常高表达。在阿尔茨海默病患者与正常脑组织样本之间、IGF2BP2 高表达与 IGF2BP2 低表达亚组的阿尔茨海默病患者之间进行比较后，我们将共享的差异表达基因作为 IGF2PB2 影响阿尔茨海默病发生的相关基因集，用于后续分析。然后，进行加权基因相关性分析，鉴定出 17 个功能模块。与阿尔茨海默病和 IGF2BP2 高表达亚组最正相关的模块主要参与细胞外基质受体相互作用、粘着斑、细胞因子-细胞因子受体相互作用和 TGF-β信号通路。之后，通过 LASSO 回归构建了一个基于枢纽基因的包含 20 个基因的模型，并通过 ROC 曲线进行验证，用于阿尔茨海默病的诊断。最后，我们初步阐明了 IGF2BP2 可以以 m6A 依赖的方式与 mRNAs 结合。本研究首次阐明了 IGF2BP2 在阿尔茨海默病中的致病作用。IGF2BP2 及其相关的 m6A 修饰可能成为阿尔茨海默病患者新的诊断和治疗靶点。
