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<p>While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer’s disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer’s disease and aging.</p>

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A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月23日

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  • Patrick W. Sheehan,
  • Stuart B. Fass,
  • Darshan Sapkota,
  • Sylvia Kang,
  • Henry C. Hollis,
  • Jennifer H. Lawrence,
  • Sohui Park,
  • Ashish Sharma,
  • Dorothy P. Schafer,
  • Ron C. Anafi,
  • Joseph D. Dougherty,
  • John D. Fryer,
  • Erik S. Musiek

摘要

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer’s disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer’s disease and aging.