Sleep Deprivation Induces Glial Dysfunction, Synaptic Loss, Metabolic Imbalance, and Cognitive Impairment in 12-Month-Old Mice: Protective Effects of D30.

Sleep deprivation (SD) has been increasingly implicated in age-related cognitive decline. However, the mechanisms linking SD duration to progressive disruption of glial homeostasis, synaptic vulnerability, and metabolic dysregulation remain poorly defined. We employed 12-month-old Thy1-EGFP and Cx3CR1-EGFP mice to investigate the effects of short-term sleep deprivation (SSD) and long-term sleep deprivation (LSD) on neuronal architecture, microglial morphology, and astrocytic homeostasis. Quantitative analyses included dendritic spine density, synaptic protein expression, glial morphological and transcriptional markers, and untargeted plasma metabolomics. The neuroprotective effects of D30, a novel small molecule compound, were also evaluated. SSD induced relatively transient oxidative stress and glial suppression, whereas LSD led to sustained reductions in dendritic spine density, synaptic protein levels, and microglial/astrocytic morphological complexity. LSD further disrupted mitochondrial metabolism, notably involving the TCA cycle, AMPK-associated signaling, and lipid homeostasis. Treatment with D30 significantly ameliorated LSD-induced deficits by preserving glial homeostatic features, restoring synaptic protein expression, maintaining dendritic spine density, and rebalancing systemic metabolism, ultimately improving cognitive performance. LSD impairs glial homeostatic integrity and synaptic stability in association with systemic metabolic dysfunction in middle-aged mice. D30 effectively alleviates these impairments, highlighting its potential as a protective intervention for chronic SD-related neurocognitive dysfunction.