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PreprintCited by 1,414Neuroinflammation and Neurodegeneration MechanismsAutophagy in Disease and TherapyGenetics, Aging, and Longevity in Model Organisms

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

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Marschallinger, Julia, Iram, Tal, Zardeneta, Macy, Lee, Song E., Lehallier, Benoit, Haney, Michael S., Pluvinage, John V., Mathur, Vidhu +10 more·2019·Nature Neuroscience
DOI 10.1101/722827PMC PMC7595134
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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 (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation 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, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to age-related and genetic forms of neurodegeneration.

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  • LD-accumulating microglia (LDAM) have phagocytosis deficits, produce excessive ROS and pro-inflammatory cytokines, and are implicated in the pathogenesis and progression of neuroinflammatory diseases.

    “LD accumulating microglia (LDAM) have phagocytosis deficits, produce excessive amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines, and are increasingly implicated in the pathogenesis and progression of neuroinflammatory diseases [17,18,19].”

    From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [18]

    The Introduction reports that lipid-droplet-accumulating microglia have phagocytosis defects, increased ROS, and elevated pro-inflammatory cytokine release. It only suggests that they might contribute to neurodegenerative diseases; the “LAM in neurodegeneration” section says their role in disease remains to be determined. The claim therefore overstates their implication in disease pathogenesis and progression. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In whole hippocampus and isolated microglia of young and aged mice, lipid droplet composition is mainly glycerolipids with only a small proportion of cholesterol.

    “Studies determining LD composition in whole hippocampus and isolated microglia of young and aged mice report mainly glycerolipids with only a small proportion of cholesterol [18].”

    From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [18]

    In “Microglia accumulate lipid droplets in the aging brain” (Fig. 1j–k; page not provided), lipid droplets from aged whole hippocampus and isolated aged microglia were mainly glycerolipids, with very little cholesteryl ester. The supplementary figure caption says young and aged microglial droplet compositions were similar, but the cited composition results do not establish the same finding for whole hippocampus from young mice. The paper reports cholesteryl esters specifically, rather than cholesterol generally. (LLM, conf=0.87)

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Authors
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., Kim, J., Tevini, J., Felder, T. K., Wolinski, H., Bertozzi, C. R., Bassik, M. C., Aigner, L., & Wyss-Coray, T.
Affiliations
  • Paracelsus Medical University (AT)
  • Stanford Medicine (US)
  • Stanford University (US)
  • Howard Hughes Medical Institute (US)
  • University of Graz (AT)
ORCID
Venue
Nature Neuroscience
Publisher
openRxiv
Published
2019-08-06
Volume
23
Issue
2
Pages
194-208
ISSN
1097-6256 (ISSN-L)
DOI
10.1101/722827
PMC
PMC7595134
OpenAlex
W3000061011
Cited by
1,414
References
1
Citations by year
2026: 293 · 2025: 300 · 2024: 264 · 2023: 190 · 2022: 158 · 2021: 142 · 2020: 66
FWCI
54.50
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Glenn Foundation for Medical Research
  • Cure Alzheimer's Fund
  • Austrian Science Fund (T736)
  • Fondation pour la Recherche Médicale
  • Universität Salzburg
  • NOMIS Stiftung
  • Karl-Franzens-Universität Graz
  • National Institutes of Health (1dp2hd084069-01)
  • National Institute on Aging (AG053015, DP1AG053015)
  • National Human Genome Research Institute (T32HG000044)
  • National Institute of General Medical Sciences (R37GM058867, R01GM058867)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2 HD084069)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
microglia, lipid droplets, brain aging, neuroinflammation, phagocytosis, reactive oxygen species, inflammatory cytokines, innate immunity, progranulin, gene regulatory networks, neurodegeneration, hippocampus, CRISPR-Cas9 screen, lipid droplet formation
MeSH terms
Aging, Animals, Brain, Humans, Inflammation, Lipids, Microglia, Mice

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