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

Marschallinger, J.; Iram, T.; Zardeneta, M.; Lee, S.; Lehallier, B.; Haney, M.; Pluvinage, J.; Mathur, V.; Hahn, O.; Morgens, D.; Kim, J.; Tevini, J.; Felder, T.; Wolinski, H.; Bertozzi, C.; Bassik, M.; Aigner, L.; Wyss-Coray, T.

doi:10.1101/722827

bioRxiv · 10.1101/722827

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

Marschallinger, J.·Iram, T.·Zardeneta, M.·Lee, S.·Lehallier, B.·Haney, M.·Pluvinage, J.·Mathur, V.·Hahn, O.·Morgens, D.·Kim, J.·Tevini, J.·Felder, T.·Wolinski, H.·Bertozzi, C.·Bassik, M.·Aigner, L.·Wyss-Coray, T.

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Abstract

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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Marschallinger, J., Iram, T., Zardeneta, M., Lee, S., Lehallier, B., Haney, M., Pluvinage, J., Mathur, V., Hahn, O., Morgens, D., Kim, J., Tevini, J., Felder, T., Wolinski, H., Bertozzi, C., Bassik, M., Aigner, L., Wyss-Coray, T.. 2019-08-06. Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain. https://doi.org/10.1101/722827

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