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Cited by 107Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

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Hughes, Craig, Choi, Minee L., Yi, Jee-Hyun, Kim, Seung-Chan, Drews, Anna, George-Hyslop, Peter St., Bryant, Clare, Gandhi, Sonia +2 more·2020·Communications Biology
DOI 10.1038/s42003-020-0792-9PMC PMC7028984
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Abstract

The molecular events causing memory loss and neuronal cell death in Alzheimer's disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD.

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  • Tlr2 participates in Aβ recognition in the brains of AD model mice.

    “Moreover, we found that genes encoding Toll-like receptors (TLRs) such as Tlr2, which participates in Aβ recognition in the brains of AD model mice (40, 41), were up-regulated in the CD11c+ microglia.”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [41]

    The Introduction describes TLR2 as a pattern-recognition receptor in a discussion of Aβ-induced inflammation, but does not establish that it recognizes Aβ in AD-model mouse brains. In Results (Fig. 1), Aβ-induced cytokine responses persisted in TLR2-knockout macrophages but not TLR4-knockout macrophages. The cited paper therefore does not support the claim’s specific setting or demonstrate the proposed TLR2 role there. (LLM, conf=0.79)

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References 29 · Cited by 107

Research works printed but not linked: 23

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Authors
Hughes, C., Choi, M. L., Yi, J.-H., Kim, S.-C., Drews, A., George-Hyslop, P. S., Bryant, C., Gandhi, S., Cho, K., & Klenerman, D.
Affiliations
  • University of Cambridge (GB)
  • The Francis Crick Institute (GB)
  • University of Bristol (GB)
  • King's College London (GB)
Corresponding author
Klenerman, David
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2020-02-18
Volume
3
Issue
1
Pages
79-79
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-020-0792-9
PMC
PMC7028984
OpenAlex
W3002969891
Cited by
107
References
29
Citations by year
2026: 11 · 2025: 23 · 2024: 19 · 2023: 13 · 2022: 19 · 2021: 13 · 2020: 9
FWCI
8.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • Explore Bristol Research (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
  • The Francis Crick Institute (cc-by)
Funders
Alzheimer's Research UK
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
amyloid-beta aggregates, Aβ42 oligomers, TLR4, Alzheimer's disease, neuronal cell death, astrocytes, TNF-α, neuroinflammation, hippocampus, TLR4 antagonist, autocrine and paracrine signaling
MeSH terms
Animals, Animals, Newborn, Cells, Cultured, Embryo, Mammalian, Male, Neurons, Signal Transduction, Amyloid beta-Peptides, Cell Death, Rats, Sprague-Dawley, Rats, Wistar, Long-Term Potentiation, Toll-Like Receptor 4, Mice, Rats, Protein Aggregation, Pathological, Protein Aggregates

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