Sleep fragmentation increased pro-inflammatory cytokines by 40% in both male and female APPknock-in mice.
disrupted sleep patterns, reducing light-phase sleep and increasing variability in both sexes.
Increased astrocyte activation, indicated by higher GFAP levels, was observed, especially in females.
Male mice exhibited decreased expression of microglial activation markers despite increased inflammation.
Distinct regional and sex-specific patterns of accumulation were noted, with females showing higher levels in the neocortex.
Medium-sized plaque density in the hippocampus was greater in females after sleep fragmentation, while males showed reduced amyloid-beta in certain fractions.
Simplified
INTRODUCTION: Sleep fragmentation often precedes Alzheimer's disease (AD) diagnosis and represents a potential modifiable risk factor, especially among women who have higher prevalence of both sleep disorders and AD.
METHODS: This study investigated how affects and (Aβ) accumulation in male and female APPknock-in mice, a physiologically relevant AD model expressing APP at normal levels. APPmice of both sexes (N=8/sex/strain, 8 months old) underwent either 5 weeks of chronic sleep fragmentation administered during the light phase using an automated sweeper system or undisturbed sleep. Sleep-wake patterns and circadian rhythms were monitored using piezoelectric sensors. Following intervention, we assessed neuroinflammatory markers via immunohistochemistry and multiplex cytokine analysis, Aβ levels in different solubility fractions, and Aβ plaque characteristics through digital pathology. SAA SAA
RESULTS: Sleep fragmentation effectively disrupted sleep patterns in both sexes, reducing light-phase sleep and increasing intradaily variability. Sleep fragmentation increased GFAP immunoreactivity in both sexes, with larger effects in females than males. Surprisingly, sleep fragmentation decreased expression of the microglial activation markers MHCII and Dectin-1 in males. Pro-inflammatory cytokines (IL-1β, CCL2, CXCL2) were significantly elevated following sleep fragmentation, with distinct regional and sex-specific patterns. In females, sleep fragmentation increased PBS-soluble and formic acid-soluble Aβ in the neocortex and medium-sized plaque density in the hippocampus, while males showed decreased detergent-soluble Aβ in the neocortex following sleep fragmentation.
DISCUSSION: Chronic sleep fragmentation exacerbates AD-related pathology in APPmice in a sex-dependent manner, with females showing greater vulnerability to Aβ accumulation and astrocyte reactivity following sleep disruption. These findings suggest that environmental sleep disruptions may contribute to the higher prevalence of AD in women and highlight the importance of addressing sleep fragmentation as a modifiable risk factor for AD. SAA
Key numbers
52.2%
Increase in GFAP Immunoreactivity
Measured increase in GFAP-positive area in the neocortex of sleep-fragmented females.
p = 0.001
Increase in Aβ Levels in Females
Statistical significance of PBS-soluble Aβ increase in female neocortex.
p = 0.017
Decrease in Detergent-Soluble Aβ in Males
Statistical significance of Aβ decrease in the neocortex of male mice.
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BFO is a co-owner of Signal Solutions, LLC, which manufactures the piezoelectric sleep monitoring equipment used in this study. He also reports NIH grants to Signal Solutions, typically with 50% subawarded to UK, but not directly related to this manuscript (but potentially synergistic). On his current STTR award, he is the PI through his UK faculty position, even though the award is to Signal Solutions. He also reports multiple conflict of interest management plans, and a UK COI committee, to help him manage these potential conflicts of interest. He receives a portion of his yearly income from Signal Solutions, that is variable, but averages roughly 25% of his yearly salary. He attends most scientific meetings paid by Signal Solutions, even when presenting UK related research, mainly because it is easier; non-financial support includes admin support from his company, to free up his time for both UK and the company; reports patent “Stimulation System Based on Mechanical Vibration for Modification and Characterization of Sleep and Behavior in Rodents”, not directly relevant to the manuscript. MJD reports honoraria for reviews of grants related to research on Alzheimer’s disease from State of Florida Department of Health. All other authors report no conflicts of interest related to this work.
