Chronic Sleep Disruption Activates the Transcriptional Unfolded Protein Response and Induces Compartment-Specific Proteomic Changes in Mice

Sleep disruption (SD) is associated with adverse brain health and increased risk of dementia, including Alzheimer's disease (AD), yet the pathological mechanisms underlying this association are not fully understood. Preclinical studies have shown that acute SD impairs cognition by altering vulnerable synapses (molecular composition, ultrastructure, and function). However, the cumulative effects of chronic SD on the adult brain and its vulnerable synapses, that might contribute to AD risk, remain poorly defined. Here, we investigated the impact of chronic SD on brain transcriptomic signatures and subcellular compartment-specific proteomic profiles to identify genes, proteins, and signaling pathways that might confer AD risk. Chronic SD induced a modest transcriptional stress response globally, whereas alterations were more pronounced in the synaptosomal (synapse-enriched P2 fractions) and whole-brain proteomes. Remarkably, chronic SD elicited unique proteomic alterations at the synaptic compartment were distinct from whole-brain effects, including increased proteins involved in synaptic vesicle endocytosis, regulation of dendritic spine morphogenesis, and regulation of long-term synaptic depression, compared to increased proteins involved in immune/inflammatory, glial responses and neuronal function at the whole-brain level. Consistent with the chronic SD-induced molecular signatures, we observed subtle ultrastructural changes in vulnerable CA1 hippocampal synapses, including reduced pre-synapse size and decreased synaptic vesicle density, which suggest that chronic SD modifies synaptic transmission and plasticity. Together, our findings indicate that chronic SD differentially impacts the brain and the synaptic proteome, nominating candidate therapeutic targets and signaling pathways for future mechanistic studies of chronic SD and how SD contributes to increased AD risk.