Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain.
Julia MarschallingerTal IramMacy ZardenetaSong E LeeDaniela BerdnikMichael S HaneyJohn V PluvinageVidhu MathurOliver HahnDavid W MorgensJustin KimJulia TeviniThomas Klaus FelderHeimo WolinskiCarolyn R BertozziMichael C BassikLudwig AignerTony Wyss-CorayPublished in: Nature neuroscience (2020)
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.
Keyphrases
- single cell
- inflammatory response
- neuropathic pain
- induced apoptosis
- genome wide
- high throughput
- endothelial cells
- crispr cas
- copy number
- fatty acid
- reactive oxygen species
- cell cycle arrest
- immune response
- oxidative stress
- lipopolysaccharide induced
- genome editing
- gene expression
- endoplasmic reticulum stress
- induced pluripotent stem cells
- dna methylation
- spinal cord injury
- white matter
- signaling pathway
- cell proliferation
- transcription factor
- blood brain barrier
- multiple sclerosis
- cerebral ischemia