Distinct microglia alternative splicing in Alzheimer's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alternative splicing (AS) is implicated in Alzheimer's disease (AD), but cell type-specific analyses are limited.
• Microglia play crucial roles in AD pathogenesis, yet their AS landscape in this disease remains underexplored.

Purpose of the Study:

• To characterize cell type-specific alternative splicing events in hippocampal microglia from an Alzheimer's disease mouse model.
• To identify novel molecular pathways and potential therapeutic targets in AD pathogenesis.

Main Methods:

• Hippocampal microglia were isolated from APP (Alzheimer's disease model) and non-transgenic mice.
• RNA sequencing data (GSE171195) were analyzed for various AS events (SE, A3SS, RI, A5SS, MXE) using rMATS and maser.
• Differential gene expression, gene ontology, and correlation analyses were performed.

Main Results:

• 95 significant AS events were identified in microglia, with skipped exons (SE) being the most prevalent type.
• Autophagy genes were predominantly affected by SE, actin depolymerization genes by alternative 3' splice sites (A3SS), and synaptic plasticity genes by retained introns (RI).
• These AS events may be driven by altered splicing factor activity in AD.

Conclusions:

• This study provides the first comprehensive analysis of microglia-specific alternative splicing in Alzheimer's disease.
• The identified AS events offer new insights into the molecular mechanisms underlying AD pathogenesis.
• These findings may pave the way for novel therapeutic strategies targeting microglia in AD.