Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity

Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimers disease, with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for Alzheimers disease, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell-type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial conditioned media driving higher neuronal firing rates than APOE3 conditioned media. Both APOE3 and APOE4 neurons increase network activity in response to conditioned media treatments, while APOE4 neurons uniquely increase presynaptic puncta with APOE4 microglial conditioned media. Conditioned media-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Lastly, increased network activity is accompanied by increased lipid droplet metabolism and blocking lipid droplet metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal lipid droplets in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.