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Cited by 121Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner

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Wong, Man Ying, Lewis, Michael, Doherty, James J., Shi, Yang, Cashikar, Anil G., Amelianchik, Anna, Tymchuk, Svitlana, Sullivan, Patrick M. +6 more·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01869-3PMC PMC7298825

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Abstract

Background: Genome-wide association studies of Alzheimer’s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. Methods: We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. Results: We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. Conclusion: 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

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Authors
Wong, M. Y., Lewis, M., Doherty, J. J., Shi, Y., Cashikar, A. G., Amelianchik, A., Tymchuk, S., Sullivan, P. M., Qian, M., Covey, D. F., Petsko, G. A., Holtzman, D. M., Paul, S. M., & Luo, W.
Affiliations
  • Weill Cornell Medicine (US)
  • Sage Therapeutics (United States) (US)
  • Washington University in St. Louis (US)
  • Veterans Health Administration (US)
Corresponding author
  • Paul, Steven M.
  • Luo, Wenjie
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-06-17
Volume
17
Issue
1
Pages
192-192
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-020-01869-3
PMC
PMC7298825
OpenAlex
W3035942478
Cited by
121
References
103
Citations by year
2026: 13 · 2025: 31 · 2024: 21 · 2023: 24 · 2022: 17 · 2021: 11 · 2020: 3 · 2019: 1
FWCI
5.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (NS090934, AG047644)
  • National Institutes of Health (MH110550)
  • JPB Foundation (NA)
  • Appel Alzheimer's disease Research institute (NA)
  • Washington University–Centene Personalize Medicine Initiative (NA)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
25-hydroxycholesterol, oxysterols, cholesterol 25-hydroxylase, microglia, IL-1β, APOE ε4, Alzheimer's disease, neuroinflammation, potassium efflux, lipopolysaccharide, TLR4, amyloid plaques
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Frontal Lobe, Humans, Hydroxycholesterols, Lipopolysaccharides, Mice, Transgenic, Steroid Hydroxylases, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Interleukin-1beta

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