Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain PMID: 31959936

Target-related Cytokines

2026-09-23

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

Nat Neurosci. 2020 Feb;23(2):194-208. doi: 10.1038/s41593-019-0566-1.

Julia Marschallinger ¹ ² ³ , Tal Iram ¹ ² , Macy Zardeneta ¹ ² , Song E Lee ¹ ² , Benoit Lehallier ¹ ² , Michael S Haney ¹ ⁴ , John V Pluvinage ¹ ² ⁵ , Vidhu Mathur ¹ ² , Oliver Hahn ¹ ² , David W Morgens ⁴ , Justin Kim ⁶ , Julia Tevini ⁷ , Thomas K Felder ⁷ ⁸ , Heimo Wolinski ⁹ , Carolyn R Bertozzi ⁶ , Michael C Bassik ³ ⁴ , Ludwig Aigner ³ , Tony Wyss-Coray ¹⁰ ¹¹ ¹² ¹³

Affiliations

1. Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA, USA.
2. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
3. Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
4. Department of Genetics, School of Medicine, and Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
5. Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
6. Department of Chemistry, Stanford ChEM-H and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
7. Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria.
8. Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria.
9. Institute of Molecular Biosciences, BioTechMed-Graz, University of Graz, Graz, Austria.
10. Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA, USA. [email protected].
11. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
12. Stanford Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
13. Department of Veterans Affairs, Palo Alto, CA, USA. [email protected].

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.