Does Chronic Sleep Fragmentation Lead to Alzheimer's Disease in Young Wild-Type Mice?

Abstract

Chronic sleep insufficiency is becoming a common issue in the young population nowadays, mostly due to life habits and work stress. Studies in animal models of neurological diseases reported that it would accelerate neurodegeneration progression and exacerbate interstitial metabolic waste accumulation in the brain. In this paper, we study whether chronic sleep insufficiency leads to neurodegenerative diseases in young wild-type animals without a genetic pre-disposition. To this aim, we modeled chronic sleep fragmentation (SF) in young wild-type mice. We detected pathological hyperphosphorylated-tau (Ser396/Tau5) and gliosis in the SF hippocampus. 18F-labeled fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET) further revealed a significant increase in brain glucose metabolism, especially in the hypothalamus, hippocampus and amygdala. Hippocampal RNAseq indicated that immunological and inflammatory pathways were significantly altered in 1.5-month SF mice. More interestingly, differential expression gene lists from stress mouse models showed differential expression patterns between 1.5-month SF and control mice, while Alzheimer's disease, normal aging, and APOEε4 mutation mouse models did not exhibit any significant pattern. In summary, 1.5-month sleep fragmentation could generate AD-like pathological changes including tauopathy and gliosis, mainly linked to stress, as the incremented glucose metabolism observed with PET imaging suggested. Further investigation will show whether SF could eventually lead to chronic neurodegeneration if the stress condition is prolonged in time.

Restraint stress induced anxiety and sleep in mice

“…Exposing mice to social stress or foot-shock stress results in increased wakefulness in the initial phase, followed by an altered sleep architecture, including prolonged NREM sleep or REM sleep ( 19 – 21 ). These results indicate that stressors are pathological factors that increase the risk of disturbing sleep and emotion, which may increase the development of dementia and metabolic and cardiovascular diseases ( 22 , 23 ). Nevertheless, the role and potential regulatory mechanisms of stress-induced mood and sleep alterations have not been fully elucidated.…”

Hypocretin/orexin influences chronic sleep disruption injury in the hippocampus

“…CFS has been shown to increase microglial Iba-1 and astrocyte GFAP responses in the hippocampus in WT mice ( Ba et al, 2021 ). Here, we examined whether HCRT influences the glial responses to CFS.…”

“…In a separate study, CFS in older adults predicted reduced metabolism in the hippocampus ( Andre et al, 2019 ), supporting hippocampal vulnerability to CFS. In wild-type (WT) mice, CFS resulted in several pathological changes consistent with AD, e.g., increased phosphorylation of tau in the hippocampus and upregulation of microglial and astrocyte reactivity markers in the hippocampus and cortex ( Xie et al, 2020 ; Ba et al, 2021 ). CFS in adult rats reduced hippocampal neurogenesis and impaired spatial (hippocampal-dependent) memory performance ( Sportiche et al, 2010 ), and CFS in the APP/PS1 mouse transgenic model of AD pathology increased amyloid plaque burden in the hippocampus and cortex ( Minakawa et al, 2017 ) and increased both amyloid-β 42 (Aβ 42 ) and markers of neuroinflammation in the hippocampus but not in the cortex ( Duncan et al, 2022 ).…”

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models

“…Intriguingly, disturbed sleep is associated with cognitive disorders [ 18 ]. Indeed, early observational data from institutionalized AD patients show worse nocturnal sleep among individuals with other severe forms of dementia [ 35 ], and these changes are already exacerbated in mild cognitive impairment (MCI) [ 37 ].…”