A fair sized body of evidence shows that circadian rhythm, the daily cycle of changed gene expression and behavior in cells, is important to tissue function but becomes disrupted with age and age-related disease. The regulation of circadian rhythm is complex and occurs distinctly the central nervous system and periphery of the body, and so one of the ways in which problems arise is when different cell types and tissues fall out of synchronization of rhythm. Here, researchers show that the aggregation of misfolded amyloid-β thought to be the initiating cause of Alzheimer's disease causes disruption of circadian rhythm in supporting cells in the brain, yet another view of the complex pathology of the condition.
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.
Our data reveal that astrocytes and microglia have robust and unique circadian translatomes, that circadian gene expression patterns reprogram dramatically in the setting of amyloid pathology or aging, and that changes are cell-type specific and context dependent. The core circadian clock was generally robust in the setting of amyloid plaque pathology in bulk cortex, astrocytes and microglia, although downstream rhythms in AD-relevant gene expression underwent dramatic circadian reprogramming. However, aging caused blunting of core clock gene rhythms in microglia, but not in astrocytes.
Our findings illustrate that circadian rhythms in gene expression are highly dependent on cell type and are reprogrammed in a context-dependent manner, in some cases despite robust core clock oscillation. We find that many transcripts related to metabolism, proteostasis, and AD show rhythmic expression that can be altered by pathology, emphasizing the importance of circadian regulation of gene expression and cellular function in aging and neurodegenerative conditions.
Link: https://doi.org/10.1038/s41593-025-02067-1
View the full article at FightAging
