Microglial-Targeted GCPII Inhibition Reverses Neurocognitive Impairment and Synaptic Loss After EcoHIV Infection.

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.