Abstract
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.
Highlights
About 50 million people worldwide suffer from dementia, and one case of dementia occurs every 3 seconds [1]
Based on the Gene Expression Omnibus database (GEO), we identified m6A regulator IGF2BP2, whose increase is closely related to Alzheimer’s disease (AD)
It showed that IGF2BP2 was highly expressed in entorhinal cortex, hippocampus, postcentral gyrus and superior frontal gyrus in AD patients compared with normal tissue (Figure 1D)
Summary
About 50 million people worldwide suffer from dementia, and one case of dementia occurs every 3 seconds [1]. Though amyloid-β can be regarded as the first biomarker becoming abnormal in AD patients [10,11,12,13], both amyloid-β and tau protein deposits are required for neuropathologic diagnosis [14, 15]. One of the potential mechanisms for altered expression of ADrelated genes involves disruption of the epigenome through disease-specific changes in chromatin structure and/or transcriptional programming [17]. These include changes in DNA methylation [18, 19] and histone modification [20,21,22]. The diagnosis of AD still faces great difficulties, in which biomarkers are more important than clinical manifestations to provide a breakthrough basis [1]
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