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

• DOI: 10.1111/cns.13218
• Publication Date: 2019-09-24T10:33:29Z
• Authors: Yi Xie; Li Ba; Min Wang; Sai‐Yue Deng; Si‐Miao Chen; Li‐Fang Huang; Min Zhang; Wei Wang; Feng‐Fei Ding
• Keywords: Autophagosomes; rab7 GTP-Binding Proteins; Neurodegenerative Diseases; Recognition, Psychology; Original Articles; Endosomes; Anxiety; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cognition; 0302 clinical medicine; Memory; rab GTP-Binding Proteins; Chronic Disease; Animals; Encephalitis; Sleep Deprivation; Microglia; Lysosomes; Maze Learning; Signal Transduction; rab5 GTP-Binding Proteins

AbstractAimsInsufficient 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.