Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease
Nicholas J Constantino1,2, Riley E Irmen1, Matthew J Lanning1
1Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
Introduction:
Sleep disruption is an early feature of Alzheimer's disease (AD), but the cellular mechanisms linking amyloid pathology to sleep loss remain unclear.
Methods:
Electroencephalography/electromyography (EEG/EMG) recordings, quantitative EEG analysis, and sleep deprivation were performed in APPswe/PSEN1dE9 (APP/PS1) mice at different stages of pathology relative to normal aging. Amyloid burden and microglial density were quantified with whole-brain light-sheet microscopy. CSF1R-mediated microglial depletion explored effects of microglia on sleep loss.
Results:
Amyloid plaques caused non-rapid eye movement (NREM) sleep loss that did not worsen with increased plaque burden. Aging reduced REM sleep and eliminated sleep rebound. Amyloid pathology was associated with cortical hyperexcitability, network desynchrony, and microglial expansion extending beyond plaque-bearing regions into thalamocortical and white matter networks governing sleep-wake dynamics. Microglial depletion restored > 2 hours of sleep per day without altering amyloid burden.
Discussion:
Microglia are a causal, reversible driver of amyloid-associated sleep loss, positioning sleep and EEG-based metrics as sensitive biomarkers of presymptomatic AD.
Insights
Microglia drive sleep loss in early Alzheimer's disease (AD). Reducing microglial activity restored sleep, suggesting sleep monitoring could detect presymptomatic AD.
Area of Science:
- Neuroscience
- Sleep Medicine
- Alzheimer's Disease Research
Background:
- Sleep disruption is an early indicator of Alzheimer's disease (AD).
- The precise cellular mechanisms connecting amyloid pathology to sleep disturbances in AD are not fully understood.
Purpose of the Study:
- To investigate the link between amyloid pathology and sleep disruption in a mouse model of AD.
- To explore the role of microglia in mediating sleep disturbances associated with amyloid plaques.
Main Methods:
- Utilized electroencephalography/electromyography (EEG/EMG) and quantitative EEG analysis in APP/PS1 mice.
- Assessed amyloid burden and microglial density using light-sheet microscopy.
- Employed CSF1R-mediated microglial depletion to study microglial impact on sleep.
Main Results:
- Amyloid plaques induced non-rapid eye movement (NREM) sleep loss, independent of plaque load.
- Aging negatively impacted REM sleep and sleep rebound.
- Amyloid pathology correlated with cortical hyperexcitability, network desynchrony, and widespread microglial activation.
- Microglial depletion significantly improved sleep duration without affecting amyloid levels.
Conclusions:
- Microglia are identified as a causal and reversible factor in AD-related sleep loss.
- Sleep and EEG-based metrics show promise as sensitive biomarkers for detecting presymptomatic AD.
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