Ontology Specific Alternative Splicing Changes in Alzheimer's Disease

Alternative splicing (AS) is a common phenomenon and correlates with aging and aging-related disorders including Alzheimer's disease (AD). We aimed to systematically characterize AS changes in the cerebral cortex of 9-month-old APP/PS1 mice. The GSE132177 dataset was downloaded from GEO and ENA databases, aligned to the GRCm39 reference genome from ENSEMBL via STAR. Alternative 3 ' SS (A3SS), alternative 5 ' SS (A5SS), skipped exon (SE), retained intron (RI), and mutually exclusive exons (MXE) AS events were evaluated using rMATS, rmats2sashimiplot, and maser. Differential genes or transcripts were analyzed using the limma R package. Gene ontology analysis was performed with the clusterProfiler R package. A total of 60,705 raw counts of AS were identified, and 113 significant AS events were finally selected in accordance with the selection criteria: 1) average coverage >10 and 2) delta percent spliced in (Delta PSI) >0.1. SE was the most abundant AS event (61.95%), and RI was the second most abundant AS type (13.27%), followed by A3SS (12.39%), thereafter A5SS and MXE comprised of 12.39%. Interestingly, genes that experienced SE were enriched in histone acetyltransferase (HAT) complex, while genes spliced by RI were enriched in autophagy and those which experienced A3SS were enriched in methyltransferase activity revealed by GO analysis. In conclusion, we revealed ontology specific AS changes in AD. Our analysis provides novel pathological mechanisms of AD.

Automated summary

This study systematically characterized alternative splicing changes in the cerebral cortex of APP/PS1 mice and revealed ontology-specific alterations in Alzheimer's disease. The findings provide novel insights into the pathological mechanisms of AD.