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Microglial-Targeted GCPII Inhibition Reverses Neurocognitive Impairment and Synaptic Loss After EcoHIV Infection
Yuxin Zheng1,2,3, Meixiang Huang2,3, R Michael Maragakis2
1Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
Abstract:
HIV-associated neurocognitive impairment persists despite combination antiretroviral therapy, largely driven by chronic microglial activation that sustains neuroinflammation and neuronal injury. Activated microglia contribute to HIV-associated brain pathology by releasing proinflammatory mediators that disrupt synaptic integrity and impair cognition. N-acetylaspartylglutamate (NAAG), an abundant neuropeptide that maintains glutamatergic homeostasis, is hydrolyzed by glutamate carboxypeptidase II (GCPII) to glutamate. We previously demonstrated that reduced brain and cerebrospinal fluid NAAG levels in people living with HIV correlate with cognitive impairment, and that pharmacological GCPII inhibition with 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) elevates brain NAAG and improves cognition in EcoHIV-infected mice. To enhance brain delivery and preferentially target activated microglia, we conjugated 2-PMPA to a generation 4 hydroxyl poly(amidoamine) (PAMAM) dendrimer (D-2-PMPA). Our findings demonstrate that D-2-PMPA achieves preferential microglial drug delivery, resulting in a >600% increase in cerebrospinal fluid NAAG levels. At doses 8.3-fold lower than free 2-PMPA, this formulation reversed EcoHIV-induced deficits in social interaction, novel object recognition, and fear-conditioned memory without altering locomotor activity or anxiety-like behavior. D-2-PMPA also restored prefrontal cortex synaptic density and preserved dendritic architecture. Together, these findings demonstrate that microglia-targeted GCPII inhibition represents a potent nanotherapeutic strategy to restore synaptic integrity and cognitive function in HIV-associated neurocognitive impairment.
Insights
Targeting microglia with a novel nanotherapeutic (D-2-PMPA) effectively restored cognitive function and synaptic integrity in HIV-associated neurocognitive impairment by increasing NAAG levels.
Area of Science:
- Neuroscience
- Immunology
- Nanomedicine
Background:
- HIV-associated neurocognitive impairment persists despite treatment, driven by chronic microglial activation and neuroinflammation.
- Activated microglia release inflammatory mediators, disrupting synaptic integrity and impairing cognition.
- N-acetylaspartylglutamate (NAAG) hydrolysis by glutamate carboxypeptidase II (GCPII) impacts glutamatergic homeostasis and cognition.
Purpose of the Study:
- To develop a targeted nanotherapeutic for enhanced brain delivery and microglial targeting.
- To investigate the efficacy of microglia-targeted GCPII inhibition in restoring cognitive function in HIV-associated neurocognitive impairment.
Main Methods:
- Conjugation of GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) to a poly(amidoamine) dendrimer (D-2-PMPA) for targeted delivery.
- Administration of D-2-PMPA in EcoHIV-infected mice model.
- Assessment of cerebrospinal fluid NAAG levels, cognitive function (social interaction, novel object recognition, fear conditioning), synaptic density, and dendritic architecture.
Main Results:
- D-2-PMPA achieved preferential microglial drug delivery, increasing cerebrospinal fluid NAAG levels by over 600%.
- Significantly lower doses of D-2-PMPA reversed cognitive deficits and preserved synaptic density and dendritic architecture.
- No alterations in locomotor activity or anxiety-like behavior were observed.
Conclusions:
- Microglia-targeted GCPII inhibition using D-2-PMPA is a potent nanotherapeutic strategy.
- This approach effectively restores synaptic integrity and cognitive function in HIV-associated neurocognitive impairment.
- D-2-PMPA offers a promising therapeutic avenue for neurological complications of HIV.
