Disturbance of REM sleep exacerbates microglial activation in APP/PS1 mice
Shunjie Liu1, Yangyang Meng1, Ni Wang1
1Department of Neurology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China.
Abstract:
Although both nonrapid eye movement (NREM) sleep loss and rapid eye movement (REM) sleep loss exacerbate Alzheimer's disease (AD) progression, they exert different effects. Microglial activation can be beneficial or detrimental to AD patients under different conditions. However, few studies have investigated which sleep stage is the main regulator of microglial activation or the downstream effects of this activation. We aimed to explore the roles of different sleep phases in microglial activation and to investigate the possible effect of microglial activation on AD pathology. In this study, thirty-six 6-month-old APP/PS1 mice were equally divided into 3 groups: the stress control (SC), total sleep deprivation (TSD), and REM deprivation (RD) groups. All mice underwent a 48-hour intervention before their spatial memory was assessed using a Morris water maze (MWM). Then, microglial morphology, activation- and synapse-related protein expression, and inflammatory cytokine and amyloid β (Aβ) levels in hippocampal tissues were measured. We found that the RD and TSD groups exhibited worse spatial memory in the MWM tests. In addition, the RD and TSD groups showed greater microglial activation, higher inflammatory cytokine levels, lower synapse-related protein expression and more severe Aβ accumulation than the SC group, but there were no significant differences between the RD and TSD groups. This study demonstrates that disturbance of REM sleep may activate microglia in APP/PS1 mice. These activated microglia may promote neuroinflammation and engulf synapses but show a weakened ability to clear plaques.
Insights
Disrupting rapid eye movement (REM) sleep in Alzheimer's disease (AD) mouse models activates microglia, increasing neuroinflammation and synapse loss while impairing amyloid plaque clearance. This highlights REM sleep's crucial role in AD pathology.
Area of Science:
- Neuroscience
- Sleep Science
- Alzheimer's Disease Research
Background:
- Sleep disturbances, including nonrapid eye movement (NREM) and rapid eye movement (REM) sleep loss, are known to worsen Alzheimer's disease (AD) progression.
- Microglial activation plays a complex role in AD, potentially being beneficial or detrimental depending on the context.
- The specific impact of different sleep stages on microglial activation and subsequent AD pathology remains underexplored.
Purpose of the Study:
- To investigate the distinct roles of different sleep phases in regulating microglial activation.
- To explore the downstream consequences of sleep-phase-specific microglial activation on AD pathology.
- To determine if REM sleep deprivation or total sleep deprivation has a more significant impact on AD progression.
Main Methods:
- Utilized a 48-hour intervention in 6-month-old APP/PS1 mice, dividing them into stress control (SC), total sleep deprivation (TSD), and REM deprivation (RD) groups.
- Assessed spatial memory using the Morris water maze (MWM) test post-intervention.
- Analyzed microglial morphology, activation, synapse-related proteins, inflammatory cytokines, and amyloid-beta (Aβ) levels in hippocampal tissues.
Main Results:
- Both REM deprivation (RD) and total sleep deprivation (TSD) groups exhibited impaired spatial memory compared to the stress control (SC) group.
- RD and TSD groups showed increased microglial activation, elevated inflammatory cytokine levels, and reduced synapse-related protein expression.
- Severe Aβ accumulation was observed in RD and TSD groups, with no significant differences between these two sleep deprivation conditions.
- Activated microglia in sleep-deprived mice promoted neuroinflammation and synaptic engulfment but demonstrated reduced amyloid plaque clearance capacity.
Conclusions:
- Disturbance of REM sleep significantly activates microglia in the APP/PS1 mouse model.
- Activated microglia resulting from sleep disturbance contribute to neuroinflammation and synaptic damage.
- These findings suggest that REM sleep plays a critical role in modulating microglial function and AD pathogenesis, potentially by influencing both neuroinflammation and amyloid clearance.
