Reactive astrocytes secrete lcn2 to promote neuron death
Open accessAbstract
Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.
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Reactive ACM showed an expected increase in abundance of C3, lipocalin-2, and other reactivity markers.
“we found the expected increase in abundance of C3, lipocalin-2, and other reactivity markers in reactive ACM (Figure 1e)10.”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [10]
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- Authors
- Bi, F., Huang, C., Tong, J., Qiu, G., Huang, B., Wu, Q., Li, F., Xu, Z., Bowser, R., Xia, X.-G., & Zhou, H.
- Affiliations
- Thomas Jefferson University (US)
- Stanford Medicine (US)
- University of Massachusetts Chan Medical School (US)
- Barrow Neurological Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-02-19
- Volume
- 110
- Issue
- 10
- Pages
- 4069-4074
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3593910
- OpenAlex
- W2170485551
- Cited by
- 371
- References
- 40
- Citations by year
- 2026: 23 · 2025: 24 · 2024: 42 · 2023: 40 · 2022: 33 · 2021: 38 · 2020: 38 · 2019: 22 · 2018: 18 · 2017: 17 · 2016: 14 · 2015: 26 · 2014: 25 · 2013: 10
- FWCI
- 15.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS073829, NS072113, R21NS072696, R01NS072113, NS072696, NS073829)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- reactive astrocytes, neutrophil gelatinase-associated lipocalin, neurotoxicity, neuronal cell death, TDP-43, FUS, neurodegeneration, glial activation, astrocyte-neuron interaction, conditioned medium, neurodegenerative diseases
- MeSH terms
- Lipocalin-2, Superoxide Dismutase-1, Animals, Astrocytes, Base Sequence, DNA-Binding Proteins, Humans, Nerve Degeneration, Neurons, Neurotoxins, Recombinant Proteins, Superoxide Dismutase, Cell Death, Culture Media, Conditioned, DNA, Complementary, Animals, Genetically Modified, RNA-Binding Protein FUS, Rats, Lipocalins, Frontotemporal Lobar Degeneration
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