Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease
Abstract
Microglial activation is a key feature in Alzheimer's disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFalpha and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer's disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer's disease.
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RNA expression of TLR4 is increased in APP/PS1 mice and in brain tissue of patients with AD in association with plaque deposition.
“RNA expression of TLR4 is increased in APP/PS1 mice and in brain tissue of patients with AD in association with plaque deposition [126, 127].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [126]
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- Authors
- Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., Schulz-Schüffer, W., & Fassbender, K.
- Affiliations
- Saarland University (DE)
- Research Center Borstel - Leibniz Lung Center (DE)
- University of Szeged (HU)
- Klinikum Ludwigshafen (DE)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2007
- Volume
- 20
- Issue
- 6
- Pages
- 947-956
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2076260194
- Cited by
- 543
- References
- 7
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 25 · 2023: 26 · 2022: 36 · 2021: 47 · 2020: 38 · 2019: 34 · 2018: 24 · 2017: 29 · 2016: 28 · 2015: 19 · 2014: 41 · 2013: 32 · 2012: 31
- FWCI
- 13.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cellular Physiology and Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- 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
- TLR4, Alzheimer's disease, neuroinflammation, microglial activation, innate immunity, MD-2, CD14, neurotoxicity, interleukin-6, TNF-α, nitric oxide, APP transgenic mice, amyloid plaques
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Gene Expression Regulation, Humans, Inflammation, Mice, Transgenic, Monocytes, Neurons, RNA, Messenger, Amyloid beta-Peptides, Microglia, Lipopolysaccharide Receptors, Toll-Like Receptor 4, Lymphocyte Antigen 96, Mice
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