TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation
Abstract
Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer’s disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741–744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer’s amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer’s disease pathogenesis.
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In APP23 transgenic mice, TLR2 on microglia co-localizes with Aβ plaques, and Aβ aggregates can bind to and activate microglia through the TLR2 receptor.
“In APP23 transgenic mice, TLR2 on microglia was shown to co-localize with Aβ plaques,283 and Aβ aggregates can bind to and activate microglia through the TLR2 receptor.284”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [284]
TLR2 interacts with aggregated Aβ and reduces the microglial neuroinflammatory response triggered by aggregated Aβ.
“TLR2 can interact with aggregated Aβ and reduce microglial neuroinflammatory response triggered by aggregated Aβ [368].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [368]
TLR2 deficiency enhances microglia-dependent Aβ phagocytic uptake.
“In addition, TLR2 deficiency can enhance microglia-dependent Aβ phagocytic uptake [368].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [368]
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Ganz, T., Fainstein, N., & Ben-Hur, T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00559-3 · Cited by 39 · see citing works
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32 · see citing works
Toll-like receptor 2 confers partial neuroprotection during prion disease
Carroll, J. A., Race, B., Williams, K., & Chesebro, B. (2018) · PLOS ONE · doi:10.1371/journal.pone.0208559 · Cited by 22 · see citing works
Kumbol, V., Ivanov, A., McGurran, H., Schüler, J., Zhai, Y., Ludwik, K., Hinkelmann, L., Brehm, M., Krüger, C., Küchler, J., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02199-8 · Cited by 8 · see citing works
- Authors
- Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rübe, C. E., Walter, J., Heneka, M. T., Hartmann, T., Menger, M. D., & Fassbender, K.
- Affiliations
- Saarland University (DE)
- University of Applied Sciences Kaiserslautern (DE)
- Radboud University Nijmegen (NL)
- University of Szeged (HU)
- University of Bonn (DE)
- Corresponding author
- Liu, Shirong
- Liu, Yang
- Hao, Wenlin
- Wolf, Lisa
- Walter, Jochen
- Fassbender, Klaus
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-01
- Volume
- 188
- Issue
- 3
- Pages
- 1098-1107
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2118804183
- Cited by
- 439
- References
- 52
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 41 · 2023: 38 · 2022: 36 · 2021: 52 · 2020: 30 · 2019: 45 · 2018: 37 · 2017: 21 · 2016: 26 · 2015: 19 · 2014: 20 · 2013: 22 · 2012: 11
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- 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
- TLR2, amyloid-beta, amyloid-beta 42, Alzheimer's disease, microglia, neuroinflammation, macrophage polarization, phagocytosis, TLR1, TLR6, ligand-receptor interactions, macrophages
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Humans, Macrophages, Mice, Transgenic, Phagocytosis, Amyloid beta-Peptides, Microglia, Neurogenic Inflammation, Toll-Like Receptor 1, Toll-Like Receptor 2, Toll-Like Receptor 6, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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