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 lipid structures are often assumed to be 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, from microglia in the PS19 mouse model of tauopathy. We observed that microglial DGAT KO exacerbated neurodegeneration, induced behavioral deficits, and increased the accumulation of brain cholesterol esters in male PS19 mice. Myeloid cell lipids appeared to largely localize to endosomes/lysosomes not LDs, even in control PS19 mice. Our results suggest that microglial DGAT-dependent LD biogenesis is adaptive in advanced tauopathy. Furthermore, the bulk of the lipidic accumulations in brain myeloid cells do not correspond to true LDs, which has important implications for the development of lipid-modulating therapies for neurodegenerative diseases. Overall design: snRNA-seq profiling of PU.1+ nuclei from 9.5-month-old WT (CfD) and PS19 (PCfD) mice heterozygous for Cx3cr1-CreERT2 and homozygous for floxed DGAT1 and DGAT2 alleles that were treated with tamoxifen or oil at 3 months of age. CfD-OIL, CfD-TAM, PCfD-OIL, and PCfD-TAM