Evidence map›Paper›PMID 42427142›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026

Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery.

Yuto Hasegawa, Hiroki Kawai, Robyn Wiseman, Gianluca Ursini, Hannah Alton, Feiyi Xiong, Sohan Gummadi, Naomi Mao, Kyle Mailhot, Yannan Li and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Yuto HasegawaDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hiroki KawaiDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Robyn WisemanJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Gianluca UrsiniDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hannah AltonDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Feiyi XiongDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sohan GummadiDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Naomi MaoDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Kyle MailhotDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Yannan LiDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Xiaolei ZhuDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Tomoyo SawadaLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
Barbara SlusherDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Atsushi KamiyaDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.ORCID https://orcid.org/0000-0002-4274-5567

Funding

Cell Science Research FoundationJapan Science and Technology Agency PRESTO JPMJPR2528Kanae Foundation for the Promotion of Medical ScienceMitsui Sumitomo Insurance Welfare FoundationNakatomi FoundationNCCIH NIH HHS AT010984NIA NIH HHS AG065168NIDA NIH HHS DA060630NIMH NIH HHS MH135895NIMH NIH HHS MH136297Teraoka Memorial FoundationWesco Science Foundation
6 · The paper itself

Abstract

introductionPerioperative neurocognitive disorder is a common and debilitating complication in the elderly, yet its cellular and molecular mechanisms in the aging brain remain poorly understood.

methodsUsing 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.

resultsAbdominal 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.

Indexed as

AgingAstrocytesBrainGlutamate Carboxypeptidase IIGlymphatic SystemAnimalsAquaporin 4FemaleGlutamic AcidHippocampusMaleMiceMice, Inbred C57BLAquaporin 4Glutamate Carboxypeptidase IIGlutamic Acidagingastrocytesglutamate carboxypeptidase IIglymphatic systemperioperative neurocognitive disordersex differences

Identifiers

PMID42427142
PMCPMC13351328

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.