Analyses of astrocyte-neuron lactate shuttle transporter levels in brain tissues from people with HIV-associated neurocognitive impairment and Alzheimer’s disease

Objectives: With the success of antiretroviral therapy (ART), people with HIV (PWH) are living longer. As they age, they increasingly face age-related comorbidities, including neurodegenerative conditions. The astrocyte-neuron lactate shuttle (ANLS) is a key mechanism that couples astrocytic glycolysis to neuronal oxidative metabolism, ensuring an adequate energy supply for synaptic activity. Disruption of this system has been implicated in both Alzheimer's disease (AD) and HIV-associated neurocognitive impairment (HIV-NCI), conditions characterized by some overlapping cognitive deficits yet distinct pathological drivers. Methods: We investigated the expression of major ANLS transporters, including glucose transporters (GLUT1, GLUT3) and monocarboxylate transporters (MCT1, MCT2, MCT4), in postmortem frontal cortex from individuals with AD and PWH. There were two HIV cohorts based on viral suppression (suppressed/non-suppressed), and both were stratified by neurocognitive status (neurocognitively normal/neurocognitively impaired), while AD participants were compared to cognitively healthy participants. Quantitative immunoblotting and immunofluorescence imaging characterized disease-specific alterations. Results: and MCT4 were downregulated, while virally suppressed (VS) PWH maintained preserved expression. Correlation analyses revealed strong GLUT3-MCT1 coupling in AD, suggestive of coordinated neuronal-astrocytic adaptation, but disrupted GLUT1-MCT4 relationships in VNS PWH, reflecting ANLS uncoupling under viremia. Conclusions: These findings identify shared and distinct patterns of metabolic disruption: degeneration-driven ANLS failure in AD versus inflammation-driven uncoupling in HIV-NCI.