Abstract
INTRODUCTION
Perioperative neurocognitive disorder is a common and debilitating complication in the elderly, yet its cellular and molecular mechanisms in the aging brain remain poorly understood.
METHODS
Using aged mice, we examined the impact of abdominal surgery on cognition, glymphatic activity, and astrocyte function. Sex-dependent mechanisms were investigated by integrating single-cell RNA sequencing with astrocyte-specific genetic and pharmacological manipulation.
RESULTS
Abdominal surgery induced male-specific deficits in recognition and spatial memory, reduced hippocampal glymphatic influx, and glutamate accumulation in aged mice. These changes were associated with male-specific upregulation of glutamate signaling in a distinct astrocyte subpopulation, enhanced astrocytic glutamate carboxypeptidase II (GCPII) activity, and loss of aquaporin-4 (AQP4) polarization. Astrocyte-specific GCPII knockdown rescued cognitive deficits and hippocampal glymphatic influx, consistent with pharmacological GCPII inhibition ameliorating glutamate levels, AQP4 polarization, and cognitive performance.
DISCUSSION
These findings identify astrocytic GCPII-mediated glutamate dysregulation as a mechanism contributing to sex-specific postoperative cognitive vulnerability in aging.
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This post is Copyright: | July 10, 2026
Neuro-Dementia