Journal
NATURE NEUROSCIENCE
Volume 23, Issue 2, Pages 194-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41593-019-0566-1
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Funding
- FWF Hertha-Firnberg Postdoctoral program [T736-B24]
- NIH [R37 GM058867]
- Stanford Neuroscience Institute Brain Rejuvenation Project Award [1DP2HD084069-01]
- NIH Director's New Innovator Award [1DP2HD084069-01]
- Department of Veterans Affairs
- National Institute on Aging [DP1-AG053015]
- NOMIS Foundation
- Glenn Foundation for Medical Research
- Cure Alzheimer's Fund
- Nan Fung Life Sciences Aging Research Fund
- PMU-FFF [E-16/23/117-FEA]
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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' (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is 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 (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration. Microglia in the aging hippocampus accumulate lipid droplets, and are functionally impaired and inflamed. Lipid droplet formation in microglia is regulated by genes linked to neurodegeneration such as progranulin.
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