HIV and cocaine use leads to loss of astrocyte neurotrophic support and impaired lipid homeostasis in the brain

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Summary Tight metabolic coupling between astrocytes and neurons involves astrocytes sensing neuronal stress and responding by taking up lipid-like particles containing excess peroxidated fatty acids (FA) generated during stress. During stressful conditions, the generation of reactive oxygen species (ROS) induce the peroxidation of FA in neurons. Neurons are highly sensitive to toxic peroxidated FA and unlike astrocytes, neurons have a low capacity to form lipid droplets (LD) to encase the toxic FA. Moreover, neuronal mitochondria are unable to efficiently consume FAs as an energy source. Thus, neurons expel lipid-like particles carrying the FAs. Astrocytes endocytose lipid-like particles with FA, deliver them to the ER for packaging into lipid droplets (LD) to protect the cell from the toxic FAs. LD also provide a conduit for delivery of FA to astrocyte mitochondria for use as an alternative energy source during stress. In normal conditions, astrocytes use glucose rather than FA as their main source of reserve energy under normal conditions. Metabolic coordination between astrocytes and neurons is critical for CNS functioning and lipid homeostasis. However, changes in astrocyte-neuron coupling for lipid metabolism in response to HIV and cocaine use is unknown. It is known that toxic, peroxidated fatty acids (FAs) produced and expelled by stressed neurons are transferred to astrocytic lipid droplets (LD) by lipoprotein particles. Astrocytes consume the FAs stored in LD via mitochondrial β-oxidation. Thus, metabolism of neuron-derived FA metabolism by astrocytes protects neurons from FA toxicity. Disruption of this tightly coordinated coupling to metabolize FAs likely contributes to the increased astrocytic energy metabolism and neuronal deficit reported during detrimental synergy between HIV infection and cocaine use.