Cocaine Upregulates Microglial Lipid Droplet Formation Through Increasing Lipid Synthesis Activity In Vitro and In Vivo

A novel subtype of microglia, lipid droplet accumulation microglia (LDAMs), has been identified in the aged brain, which is characterized by sustained inflammation and senescent-like phenotypes. LDAMs are deeply involved in promoting brain aging as well as the pathogenesis of multiple neurodegenerative diseases. Cocaine can alter brain lipidomic profiles, induce microglial activation, and accelerate brain aging. This suggests that cocaine might affect microglial lipid metabolism, which ultimately aggravates aging-related neurological disorders in people with addictions. In this study, we explored the effects of cocaine on microglial lipid metabolism. Our results showed that chronic cocaine administration altered brain lipid profiles and increased LDAM formation in vivo. The increase in LDAMs was accompanied by the upregulation of the senescent marker p53 in the brain. Cocaine also increased lipid droplet (LD) formation in BV2 microglia and primary microglia in vitro. A mechanism study revealed that cocaine increased the levels of SREBP1/2, HMGCR, DGAT1, and FASN, which are critical for lipid synthesis. Overall, our findings demonstrate that cocaine increases LDAM formation in vitro and in vivo. These results indicate that targeting microglia lipid metabolism might be a promising therapeutic approach to mitigate aging-related neurological syndromes in people with cocaine addictions.