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Cited by 591Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsImmune Response and Inflammation

CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation

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Reed-Geaghan, Erin G., Savage, Julie C., Hise, Amy G., Landreth, Gary E.·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.3158-09.2009PMC PMC2778845
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Abstract

Microglia are the brain's tissue macrophages and are found in an activated state surrounding beta-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar beta-amyloid (fAbeta) through an ensemble of surface receptors composed of the alpha(6)beta(1) integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of Abeta requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fAbeta is reliant upon CD14, which act together with TLR4 and TLR2 to bind fAbeta and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fAbeta-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAbeta-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IkappaBalpha following fAbeta. These data indicate these innate immune receptors function as members of the microglial fAbeta receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.

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  • Within plaque-associated microglia, Aβ fibrils upregulate microglial cytokine, chemokine and ROS production via TLR4 signaling.

    “Within plaque-associated microglia, Aβ fibrils upregulate microglial cytokine, chemokine and ROS production via TLR4 signaling [123, 124].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [123]

    The Results section on ROS production reports that fibrillar Aβ increased ROS in wild-type microglia but not TLR4-deficient microglia. The Discussion also reports prior findings that blocking TLR4 prevented fibrillar Aβ-induced IL-6 and TNF-α production. Our copy does not establish chemokine production through TLR4 or show these responses specifically in plaque-associated microglia; it notes that the study used microglia derived from neonatal animals. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The fibrillar and oligomeric Aβ-amyloid-induced neuroinflammatory response has been linked to TLR4.

    “Similarly, the fibrillar and oligomeric A β -amyloid-induced neuroinflammatory response has been linked to TLR4 as well (Reed-Geaghan et al., 2009; Wang et al., 2018).”

    From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Reed-Geaghan et al., 2009

    The Discussion links TLR4 to microglial activation and inflammatory signaling induced by fibrillar Aβ. The paper studies fibrillar Aβ, not oligomeric Aβ, so it does not support that part of the jointly cited claim. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., & Landreth, G. E.
Affiliations
  • Case Western Reserve University (US)
  • Case Comprehensive Cancer Center (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-09-23
Volume
29
Issue
38
Pages
11982-11992
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.3158-09.2009
PMC
PMC2778845
OpenAlex
W2130145174
Cited by
591
References
10
Citations by year
2026: 27 · 2025: 26 · 2024: 47 · 2023: 36 · 2022: 29 · 2021: 35 · 2020: 41 · 2019: 30 · 2018: 34 · 2017: 28 · 2016: 37 · 2015: 34 · 2014: 38 · 2013: 34 · 2012: 41
FWCI
24.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Health Assistance Foundation
  • National Institutes of Health
  • National Institute on Aging (5 T32 AG0071, AG16047, R01AG016740)
  • National Institute of Neurological Disorders and Stroke (F31NS057867)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
microglial activation, CD14, TLR2, TLR4, Alzheimer's disease, innate immune receptors, reactive oxygen species, phagocytosis, p38 MAPK, IκBα phosphorylation
MeSH terms
Animals, Cells, Cultured, Macrophage Activation, Mice, Inbred C57BL, Phagocytosis, Protein Binding, Signal Transduction, Amyloid beta-Peptides, NF-kappa B, Reactive Oxygen Species, Microglia, Mice, Knockout, Lipopolysaccharide Receptors, p38 Mitogen-Activated Protein Kinases, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice

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