Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain
Authors: Justin Kim
Michael S Haney
Michael C Bassik
Carolyn R Bertozzi
Macy Zardeneta
John V Pluvinage
Oliver Hahn
Julia Tevini
Tal Iram
Thomas K Felder
Heimo Wolinski
Song E Lee
Ludwig Aigner
Benoit Lehallier
David W Morgens
Tony Wyss-Coray
Vidhu Mathur
Julia Marschallinger
Journal: Nature Neuroscience (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Microglia; aging; lipid droplets; neurodegenerative diseases; phagocytosis
Affiliations: Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA, USA., Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA., Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria., Department of Genetics, School of Medicine, and Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA., Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA., Department of Chemistry, Stanford ChEM-H and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria., Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria., Institute of Molecular Biosciences, BioTechMed-Graz, University of Graz, Graz, Austria., Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA, USA. ., Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. ., Stanford Neurosciences Institute, Stanford University, Stanford, CA, USA. ., Department of Veterans Affairs, Palo Alto, CA, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 5h contains a possible image duplication  , 
 Figures 3b and 5h contain possible data duplication.  , 
 Figure 1k u2013 the sum of percentages is greater than 100% e.g. 48.8+1.1+27.7+9.8+3.8+9.9 = **101.1** 52.7+0.7+27.1+7.2+4.9+8.1= 100.7 Could the authors check this please?  , 
 we are in the process of correcting the error which occurred due to erroneous copying from a master data file. We apologize for the mistake.  , 
 we are in the process of fixing this mistake also with the journal. In the pie charts we had the  Ceramids (Ce) included into the group  other at the beginning. Then decided to visualize the ceramids separately. So the % of the others is the value minus the ceramids (8.8% for Hippocampus; 7.4% for Microglia). ,