Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer's disease model

Area of Science:

• Neuroscience
• Chronobiology
• Genomics

Background:

• Diurnal rhythms regulate brain functions, aligning them with the light-dark cycle.
• These rhythms are disrupted in Alzheimer's disease (AD), but their regional organization is unclear.
• Understanding regional diurnal transcription is crucial for AD pathogenesis research.

Purpose of the Study:

• To map the spatial organization of diurnal transcription across the mouse brain.
• To investigate regional differences in rhythmic transcription in healthy and AD models.
• To identify early molecular changes in AD pathogenesis related to diurnal rhythms.

Main Methods:

• Large-scale spatial transcriptomics was employed to profile gene expression over 24 hours.
• Transcriptomic data was analyzed across cortical and subcortical regions of the mouse brain.
• The APP23 mouse model was used to study diurnal transcription in an AD context.

Main Results:

• Significant regional variations in diurnal transcription were observed across the mouse brain.
• Distinct oscillatory patterns were identified in different cortical areas and along the rostro-caudal axis.
• Early, region-specific disruption of diurnal transcription was detected in AD model brains before significant amyloid pathology.

Conclusions:

• Brain diurnal rhythms possess a spatially organized architecture.
• Early disruption of regional diurnal transcription is an emergent feature of Alzheimer's disease pathogenesis.
• These findings provide insights into the molecular timing mechanisms affected in AD.