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IL-6 Mediated Degeneration of Forebrain GABAergic Interneurons and Cognitive Impairment in Aged Mice through Activation of Neuronal NADPH Oxidase
Open accessAbstract
BACKGROUND: Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. METHODS AND FINDINGS: We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6(-/-) mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFkappaB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. CONCLUSIONS: Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.
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“IL-6 is likely signaling through STAT3 [96].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [96]
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Metadata
- Authors
- Dugan, L. L., Ali, S. S., Shekhtman, G., Roberts, A. J., Lucero, J., Quick, K. L., & Behrens, M. M.
- Affiliations
- University of California San Diego (US)
- Scripps Research Institute (US)
- Corresponding author
- Dugan, Laura L.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-05-13
- Volume
- 4
- Issue
- 5
- Pages
- e5518
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2678193
- OpenAlex
- W2000833088
- Cited by
- 165
- References
- 66
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 9 · 2019: 11 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 11 · 2014: 11 · 2013: 13 · 2012: 7
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health (NS057096)
- National Institute on Aging (K25AG026379, R21AG030320, AG030320)
- National Institute of Neurological Disorders and Stroke (P30NS057096, NS057096)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Antioxidants, Aging, Portulaca oleracea
- Keywords
- interleukin-6, brain aging, GABAergic interneurons, parvalbumin interneurons, NADPH oxidase, superoxide, non-canonical NF-κB signaling, age-related cognitive decline, neuroinflammation, superoxide dismutase mimetic, spatial learning and memory
- MeSH terms
- NADPH Oxidase 2, Aging, Animals, Cell Nucleus, Cognition, gamma-Aminobutyric Acid, Interneurons, Membrane Glycoproteins, Mice, Transgenic, Nerve Degeneration, Neurons, Parvalbumins, Superoxide Dismutase, Synaptosomes, Interleukin-6, Prosencephalon, NADPH Oxidases, Mice
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