Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain
Top Cited Papers
- 20 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 23 (2), 194-208
- https://doi.org/10.1038/s41593-019-0566-1
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’ (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.Keywords
This publication has 59 references indexed in Scilit:
- Mitochondrial Dysfunction Induces Formation of Lipid Droplets as a Generalized Response to StressOxidative Medicine and Cellular Longevity, 2013
- Core features of frontotemporal dementia recapitulated in progranulin knockout miceNeurobiology of Disease, 2012
- Human Atherosclerotic Plaque Alternative Macrophages Display Low Cholesterol Handling but High Phagocytosis Because of Distinct Activities of the PPARγ and LXRα PathwaysCirculation Research, 2011
- Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementiaThe FASEB Journal, 2010
- Lipids in Alzheimer's disease: A century-old storyBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2010
- Lipid droplets in inflammation and cancerProstaglandins, Leukotrienes & Essential Fatty Acids, 2010
- Efficient Phagocytosis Requires Triacylglycerol Hydrolysis by Adipose Triglyceride LipaseOnline Journal of Public Health Informatics, 2010
- Adaptor Protein Sorting Nexin 17 Regulates Amyloid Precursor Protein Trafficking and Processing in the Early EndosomesJournal of Biological Chemistry, 2008
- Characteristics of frontotemporal dementia patients with a Progranulin mutationAnnals of Neurology, 2006
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959