Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice
Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These neutral lipids are often assumed to be contained in lipid droplets (LDs), and 'LD-high microglia' have generally been characterized as maladaptive. While a number of studies have been performed in cell culture and Drosophila models to characterize glial LD dynamics, it is still unclear what roles microglial LD biogenesis play in mammalian tauopathy. To address this question, we induced the deletion of diacylglycerol acyltransferases 1 and 2 (DGATs), enzymes critical for LD formation via triglyceride (TAG) synthesis, from microglia in the PS19 mouse model of tauopathy. We observed that microglial DGAT double KO exacerbated neurodegeneration, induced behavioral deficits, and increased the abundance of brain cholesteryl esters in male PS19 mice. Myeloid cell lipid accumulations appeared to largely localize to endosomes/lysosomes not LDs in PS19 mice at baseline and this phenotype was exacerbated upon DGAT KO. Our results suggest that microglial DGAT-dependent TAG/LD biogenesis is adaptive in advanced tauopathy. Furthermore, the bulk of the lipid accumulation in brain myeloid cells may not correspond to true LDs in this tauopathy model, which has important implications for the development of lipid-modulating therapies for neurodegenerative diseases.