Chronic sleep fragmentation shares similar pathogenesis with neurodegenerative diseases: Endosome-autophagosome-lysosome pathway dysfunction and microglia-mediated neuroinflammation.

Yi Xie,Li Ba,Wei Wang,Min Zhang,Li‐Fang Huang,Sai‐Yue Deng,Min Wang,Feng‐Fei Ding,Si‐Miao Chen

doi:10.1111/cns.13218

Abstract

AimsInsufficient sleep has been found to result in varying degrees of cognitive impairment and emotional changes. Sleep was reported probably responsible for cleaning metabolic wastes in brain by increasing extracellular bulk flow. Herein, we propose that chronic sleep insufficiency in young adult wild‐type mice is also linked with dysfunction of intracellular protein degradation pathways and microglia‐mediated neuroinflammation, which are potentially important mechanisms in the initiation of neurodegeneration.MethodsWe applied the chronic sleep fragmentation (CSF) model to induce chronic sleep insufficiency in wild‐type mice. After 2 months of CSF, cognitive function, amyloid‐β accumulation, dysfunction of endosome‐autophagosome‐lysosome pathway, and microglia activation were evaluated.ResultsFollowing CSF, impairment of spatial learning and memory, and aggravated anxiety‐like behavior in mice were identified by behavioral experiments. Increased intracellular amyloid‐β accumulation was observed in cortex and hippocampus. Mechanistically, CSF could significantly enhance the expression of Rab5 (early endosome marker), Rab7 (late endosome marker), as well as LC3B (autophagosome marker), and autophagy‐positive regulatory factors in brain detected by immunofluorescent staining and Western blot. In addition, activation of microglia was evident by enhanced CD68, CD16/32, and CD206 levels after CSF treatment.ConclusionsChronic sleep fragmentation could initiate pathogenetic processes similar to the early stage of neurodegeneration, including dysfunction of endosome‐autophagosome‐lysosome pathway and microglia‐mediated neuroinflammation. Our findings further strengthen the link between chronic sleep insufficiency and the initiation of neurodegeneration even if lack of genetic predisposition.

Highlights

Lack of sleep has already become a pervasive trend in many popula‐ tions in our society, mostly due to electronic devices use, excessive workload, and life stress
We found that chronic sleep fragmentation (CSF) could induce pathogenic processes similar to those of early‐stage Alzheimer's disease (AD)
In addition to impaired cognitive function, which was evident by behavior tests, we found intracellular Aβ accumulation after 2‐month CSF

Summary

| INTRODUCTION

Lack of sleep has already become a pervasive trend in many popula‐ tions in our society, mostly due to electronic devices use, excessive workload, and life stress. It was recently reported that sleep was an important physiological process, during which extracellular meta‐ bolic wastes such as β‐amyloid protein were cleared via paravascular pathway.[1,12,13]. This paravascular cleaning processes were found to be significantly suppressed by sleep deprivation treatment and in AD mouse models.[14-16]. In the current study, we provided evidence that chronic sleep fragmen‐ tation (CSF) could induce similar pathogenesis of neurodegeneration in young adult wild‐type mice, involving dysfunction of intracel‐ lular protein degradation as well as microglia activation. Our data would highlight the potential risk of initiating neurodegeneration by chronic sleep insufficiency, even if in young adults without genetic predisposition of neurodegenerative diseases

| MATERIALS AND METHODS

Findings

| DISCUSSION