Aging-like changes in the transcriptome of irradiated microglia.

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Whole brain irradiation is crucial for treating brain tumors but can lead to long-term cognitive deficits.
• Microglial activation and chronic inflammation are implicated in radiation-induced brain injury.

Purpose of the Study:

• To comprehensively profile the transcriptional changes in microglia following cranial irradiation.
• To identify conserved gene expression signatures and pathways affected by irradiation.

Main Methods:

• Isolation of microglia from mouse hippocampi using fluorescence-activated cell sorting (FACS) after cranial irradiation.
• Gene expression profiling using Affymetrix arrays and RNA-sequencing (RNA-seq).
• Analysis of gene expression data using linear modeling, rank product, gene set enrichment, and weighted gene coexpression network analyses.

Main Results:

• A conserved transcriptional signature of 448 upregulated and 85 downregulated genes was identified in irradiated microglia one month post-irradiation.
• Irradiated microglia showed enrichment for inflammation (M1 macrophage genes), extracellular matrix, and blood coagulation pathways.
• Alterations in mitochondrial function were observed, and early (24-h) postradiation transcriptomes also revealed changes in apoptotic and lysosomal gene expression.

Conclusions:

• Cranial irradiation induces a distinct microglial transcriptional profile involving inflammation and unexpected pathways.
• Shared molecular mechanisms may link chronic irradiation-induced cognitive decline and cognitive aging.