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<p>Microglia, the resident immune cells of the central nervous system, undergo age-associated transcriptional and functional remodeling implicated in multiple neurodegenerative diseases. Yet bulk and single-cell short-read RNA sequencing lack the resolution to full-length transcripts, leaving the isoform landscape of aging microglia and its alternative splicing regulation incompletely defined. Here, we present an isoform-centric landscape of microglial aging generated by Nanopore long-read RNA sequencing of purified microglia from male mice across 5 ages (2, 8, 12, 16, and 20 months), complemented by single-cell isoform sequencing to map isoform usage across homeostatic and reactive microglial subpopulations, and by acute lipopolysaccharide (LPS) challenge in young (2 months) and aged (20 months) mice. Across the aging trajectory, we cataloged 108,381 transcript isoforms from 25,439 genes, including 57,647 previously unannotated isoforms, revealing isoform-resolved aging programs and aging-related transcript usage switches that were frequently uncoupled from gene-level differential expression. Leveraging isoform RNA-seq at single-cell resolution, we mapped aging-associated isoforms to disease-associated microglia (DAM) and interferon-response microglia (IRM), providing a subtype-specific reference for interrogating isoform switching across microglial states. We further delineated how aging shapes LPS-evoked isoform response and identified microglial co-expression modules linked to neurodegenerative disease risk. Together, our study provides an isoform-resolved resource of microglial state diversification and age-dependent inflammatory responsiveness, and identifies isoform changes and splicing-associated modules that merit future mechanistic validation in neuroinflammation and neurodegeneration.</p>

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Long-read sequencing reveals RNA splicing dynamics in microglial aging and inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Ze Wang,
  • ChenYang Zhao,
  • Yilai Han,
  • Yan Wang,
  • Yan Liang,
  • Xiyue Zhang,
  • Mingyang Wang,
  • Teng Chen,
  • Guoliang Chai,
  • Fei Wang

摘要

Microglia, the resident immune cells of the central nervous system, undergo age-associated transcriptional and functional remodeling implicated in multiple neurodegenerative diseases. Yet bulk and single-cell short-read RNA sequencing lack the resolution to full-length transcripts, leaving the isoform landscape of aging microglia and its alternative splicing regulation incompletely defined. Here, we present an isoform-centric landscape of microglial aging generated by Nanopore long-read RNA sequencing of purified microglia from male mice across 5 ages (2, 8, 12, 16, and 20 months), complemented by single-cell isoform sequencing to map isoform usage across homeostatic and reactive microglial subpopulations, and by acute lipopolysaccharide (LPS) challenge in young (2 months) and aged (20 months) mice. Across the aging trajectory, we cataloged 108,381 transcript isoforms from 25,439 genes, including 57,647 previously unannotated isoforms, revealing isoform-resolved aging programs and aging-related transcript usage switches that were frequently uncoupled from gene-level differential expression. Leveraging isoform RNA-seq at single-cell resolution, we mapped aging-associated isoforms to disease-associated microglia (DAM) and interferon-response microglia (IRM), providing a subtype-specific reference for interrogating isoform switching across microglial states. We further delineated how aging shapes LPS-evoked isoform response and identified microglial co-expression modules linked to neurodegenerative disease risk. Together, our study provides an isoform-resolved resource of microglial state diversification and age-dependent inflammatory responsiveness, and identifies isoform changes and splicing-associated modules that merit future mechanistic validation in neuroinflammation and neurodegeneration.