Ontology Specific Alternative Splicing Changes in Alzheimer's Disease

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Alternative splicing (AS) is a key regulatory mechanism in gene expression.
• AS alterations are implicated in aging and age-related disorders, including Alzheimer's disease (AD).

Purpose of the Study:

• To systematically characterize alternative splicing changes in the cerebral cortex of a mouse model of Alzheimer's disease (APP/PS1 mice).
• To identify specific AS events and their associated molecular functions in the context of AD pathology.

Main Methods:

• Utilized the GSE132177 dataset from public repositories.
• Analyzed alternative splicing events (A3SS, A5SS, SE, RI, MXE) using rMATS software.
• Performed differential gene expression analysis with limma and Gene Ontology (GO) analysis with clusterProfiler.

Main Results:

• Identified 113 significant AS events with stringent criteria (average coverage >10, ΔPSI >0.1).
• Skipped exon (SE) was the most prevalent AS event (61.95%), followed by retained intron (RI) (13.27%) and alternative 3' splice site (A3SS) (12.39%).
• GO analysis revealed enrichment of histone acetyltransferase (HAT) complex for SE, autophagy for RI, and methyltransferase activity for A3SS.

Conclusions:

• This study reveals ontology-specific alternative splicing alterations in Alzheimer's disease.
• The findings provide novel insights into the molecular and pathological mechanisms underlying AD through the lens of alternative splicing.