Abstract Introduction Sleep disruption (SD) negatively impacts several aspects of cognitive function and increases the risk of developing dementia, including Alzheimer’s disease (AD). Synapses are particularly vulnerable to sleep loss and therefore represent a major target to prevent cognitive dysfunction. SD impairs cognition by altering synaptic molecular composition, ultrastructure, and function. Extensive evidence indicates that SD effects are especially detrimental when sleep loss is chronic. This study aims to investigate the impact of chronic SD on brain transcriptomic and cellular compartment-specific proteomic signatures to identify genes, proteins, and pathways that might confer AD risk. Methods Male wild-type mice (6.5-month-old) were randomly assigned to an undisrupted sleep control group and an SD group (N=10/group). For chronic SD, mice were placed into automated sleep fragmentation chambers that include a swipe bar, set to move every 30 sec for six hours per day, over six weeks. Next day, mice were euthanized and brains were quickly removed, bulk brain tissue was snap frozen and crude synaptosomes (P2 fraction) were prepared immediately by differential centrifugation. RNA was isolated from frozen brain tissue and then analyzed by RNAseq to identify differentially-enriched genes (DEGs). Brain homogenate and P2 fraction proteins were then analyzed by label-free quantitative mass spectrometry to identify differentially-enriched proteins (DEPs) and biological pathways by gene set variation analysis. Results Chronic SD mainly increased the gene expression of chaperones/heat shock proteins associated with cellular stress and the unfolded protein response. In contrast with a subtle transcriptional response, the effects of chronic SD on the brain proteome were much greater (518 DEPs in homogenate). Remarkably, chronic SD exerted unique proteomic effects on the synapse (556 DEPs in P2 fraction): Increased DEPs include cognitive resilience proteins, suggesting a compensatory mechanism, while reduced DEPs include mitochondrial proteins, potentially representing synaptic energy failure. The p38 MAPK pathway, implicated in the development and progression of AD, was uniquely increased in the synaptic compartment, supporting p38 inhibition as a neuroprotective strategy for improving synaptic pathology induced by chronic SD. Conclusion These results nominate synaptic-specific candidates for future mechanistic validation that might help clarify chronic SD effects linked to synapse dysfunction and AD risk. Support (if any) NIH R01AG071587
Espinosa-Garcia et al. (Fri,) studied this question.