%0 Journal Article %A Julia Marschallinger %A Tal Iram %A Macy Zardeneta %A Song E. Lee %A Benoit Lehallier %A Michael S. Haney %A John V. Pluvinage %A Vidhu Mathur %A Oliver Hahn %A David W. Morgens %A Justin Kim %A Julia Tevini %A Thomas K. Felder %A Heimo Wolinski %A Carolyn R. Bertozzi %A Michael C. Bassik %A Ludwig Aigner %A Tony Wyss-Coray %T Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain %D 2019 %R 10.1101/722827 %J bioRxiv %P 722827 %X Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to age-related and genetic forms of neurodegeneration. %U https://www.biorxiv.org/content/biorxiv/early/2019/08/06/722827.full.pdf