Evidence map›Paper›PMID 41203503›Full record

ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2026

Targeting NAAG metabolism restores cognition and synaptic integrity in EcoHIV-infected mice.

Yuxin Zheng, Meixiang Huang, R Michael Maragakis, Peter Pietri, Yu Su, Jesse Alt, Ying Wu, Colin Finney, Diane E Peters, Xiaolei Zhu and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Article
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

12 authors.

Yuxin ZhengDepartment of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Meixiang HuangJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
R Michael MaragakisJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Peter PietriJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yu SuJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jesse AltJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ying WuJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Colin FinneyJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Diane E PetersJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xiaolei ZhuJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rana RaisJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Barbara S SlusherJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Despite effective antiretroviral therapy, many people living with HIV (PLH) experience cognitive impairments, particularly in executive function and working memory. These deficits have been linked to dysregulation of brain circuits involving the neuropeptide N-acetyl-aspartyl glutamate (NAAG), which is catabolized by the enzyme glutamate carboxypeptidase II (GCPII). Inhibiting GCPII elevates brain NAAG levels and improves cognition in preclinical models. In prior magnetic resonance spectroscopy (MRS) studies, we demonstrated that higher brain NAAG levels in PLH correlate with better cognitive performance, highlighting NAAG as a potential biomarker and GCPII as a potential therapeutic target. In this study, we used EcoHIV-infected mice to model HIV-associated neurocognitive disorders and evaluated the therapeutic potential of the selective GCPII inhibitor 2-PMPA. We found that 2-PMPA treatment increased cerebrospinal fluid (CSF) NAAG levels by 800 ​% and reversed EcoHIV-induced deficits in social interaction, recognition memory, and fear conditioning, without affecting general locomotion or anxiety-like behavior. Furthermore, 2-PMPA restored synaptic density and preserved dendritic structure in EcoHIV-infected mice, indicating a neuroprotective effect. These findings provide strong evidence that GCPII inhibition represents a viable therapeutic strategy for HIV-associated cognitive dysfunction by elevating NAAG and protecting neural circuits critical for cognition.

Indexed as

AIDS Dementia ComplexCognitionDipeptidesGlutamate Carboxypeptidase IIHIV InfectionsSynapsesAnimalsMaleMiceMice, Inbred C57BLOrganophosphorus Compounds2-(phosphonomethyl)pentanedioic acidDipeptidesGlutamate Carboxypeptidase IIisospaglumic acidOrganophosphorus CompoundsCognitionEcoHIVGCPIIHIVNAAGSynapse

Identifiers

PMID41203503
PMCPMC12976482

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
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.