Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery
Year: 2026
Type: article
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.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71666
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: Cell Science Research Foundation, Nakatomi Foundation, Mitsui Sumitomo Insurance Welfare Foundation, Wesco Science Foundation, Kanae Foundation for the Promotion of Medical Science, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Center for Complementary and Integrative Health
Awards: Exploring a natural product to modulate aberrant gut bacterial-fungal interactions as pathological mechanisms underlying HIV-associated depression, G2486338493, G3369724511, Targeting age and gender-dependent microglia-mediated mechanisms underlying postoperative cognitive impairment for treatment of delirium in the elderly, G621767444, G789798130, G8504683028, Microglia-targeted glutaminase inhibition forthe treatment of chronic stress-associated depression, Microglia-mediated adverse effect of cannabis on prefrontal cortex maturation and cognitive function, Impact of the olfactory system on higher brain function and schizophrenia
OpenAlex ID: W7167884079