Reconstructed Cell-Type Specific Rhythms in Human Brain link Alzheimer's Pathology, Circadian Stress, and Ribosomal...

Area of Science:

• Neuroscience
• Molecular Biology
• Chronobiology

Background:

• Alzheimer's disease (AD) is known to disrupt behavioral circadian rhythms.
• The impact of AD on molecular circadian rhythms within the human brain remains poorly understood.

Purpose of the Study:

• To investigate the effects of Alzheimer's disease on cell-type specific molecular circadian rhythms in the human brain.
• To identify specific molecular pathways and cellular processes affected by circadian rhythm disruption in AD.

Main Methods:

• Utilized single-nucleus RNA sequencing on post-mortem cortical samples from individuals with and without AD dementia.
• Informatical estimation of circadian phases for 409 individuals.
• Reconstruction of circadian gene expression profiles across different brain cell types.
• Comparative analysis with APP/PS1 mouse models.

Main Results:

• Core circadian clock rhythms were largely preserved in AD brains.
• Significant disruption of cell-type specific circadian output rhythms was observed.
• Rhythms related to ribosomal biogenesis and oxidative phosphorylation were dampened across multiple cell types in AD.
• APP/PS1 mice exhibited similar losses in ribosomal gene expression rhythms and reduced protein translation.

Conclusions:

• Alzheimer's disease alters cell-type specific circadian output rhythms in the brain.
• Disrupted ribosomal gene expression rhythms are a notable feature of Alzheimer's disease.
• Altered translation processes may contribute to circadian variability observed in AD patients.