Alzheimer's disease (AD) is the most common cause of dementia worldwide (Urrestarazu and Iriarte, 2016), and sleep disturbance plays a central role in the pathogenesis and progression of AD (Peter-Derex et al., 2015). Both human and rodent studies suggest that sleep disruption increases the burden of amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation, which are considered the major pathological changes in AD (Uddin et al., 2020). Sleep usually occurs in two different phases that may have different functions: rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep (American Academy of Sleep Medicine, 2007). While REM sleep and NREM sleep exert different functions, both regulate memory consolidation (Brown et al., 2012, Uddin et al., 2020).

Microglia, which originate from erythromyeloid progenitor cells and migrate into the brain, where they propagate and ramify, are some of the most important immune cells in the brain parenchyma (Ginhoux and Prinz, 2015). Microglial function is a “double-edged sword” in AD. On the one hand, microglia exert protective effects by restraining the accumulation of Aβ and engulfing Aβ plaques or other neurotoxic substances, thus preventing the progression of AD (Hansen et al., 2018). On the other hand, overactivated microglia are deleterious in AD because they can secrete inflammatory factors and eliminate neuronal synapses (Hansen et al., 2018).

Some studies have suggested that microglia may show alterations in morphology and mRNA/protein levels that indicate activation in response to acute or chronic sleep deprivation (Bellesi et al., 2017, Tuan and Lee, 2019, Deurveilher et al., 2021). However, the corresponding studies had several limitations. First, they did not abolish NREM or REM to explore which phase primarily activates microglia. Second, most of them involved experiments on C57BL/6J mice instead of AD models; thus, they failed to explore the relationships between microglial activation and AD progression, i.e., whether the activated microglia play a protective role by engulfing neurotoxic Aβ plaques or play a detrimental role by triggering inflammation and eliminating synapses.

This study was designed to clarify this issue given the conclusions and limitations of previous research. We used 6-month-old APP/PS1 mice as AD models and subjected them to sleep deprivation to investigate the relationships between disturbance of the different sleep stages and microglial alterations. We aimed to elucidate (a) whether NREM sleep disturbance or REM sleep disturbance plays a greater role in regulating microglial activation and (b) the impact of activated microglia on inflammation, synapses and Aβ plaques.