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Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

By Julia Marschallinger, Tal Iram, Macy Zardeneta, Song E Lee, Benoit Lehallier, Michael S. Haney, John V. Pluvinage, Vidhu Mathur, Oliver Hahn, David W Morgens, Justin Kim, Julia Tevini, Thomas K. Felder, Heimo Wolinski, Carolyn R Bertozzi, Michael C Bassik, Ludwig Aigner, Tony Wyss-Coray

Posted 06 Aug 2019
bioRxiv DOI: 10.1101/722827

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.

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