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

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.