The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Imbalance of microglial TLR4/TREM2 in LPS-treated APP/PS1 transgenic mice: a potential Link between Alzheimer's disease and systemic inflammation
Abstract
Clinically, superimposed systemic inflammation generally has significant deleterious effects on the Alzheimer's disease (AD) progression. However, the related molecular mechanisms remain poorly understood. Microglial toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) are two key regulators of inflammation that may play an essential role in this complex pathophysiological process. In this study, intraperitoneal injection of lipopolysaccharide (LPS) into APP/PS1 transgenic AD model was used to mimic systemic inflammation in the development of AD. Initial results from the cortex showed that compared with wild-type mice, APP/PS1 mice exhibited elevated gene and protein expression levels of both TLR4 and TREM2 with different degree. Interestingly, after LPS treatment, TLR4 expression was persistently up-regulated, while TREM2 expression was significantly down-regulated in APP/PS1 mice, suggesting that the negative regulatory effect of TREM2 on inflammation might be suppressed by LPS-induced hyperactive TLR4. This imbalance of TLR4/TREM2 contributed to microglial over-activation, followed by increased neuronal apoptosis in the cortex of APP/PS1 mice; these changes did not alter the expression level of Aβ 1-42. Similar alterations were observed in our in vitro experiment with β-amyloid 1-42 (Aβ 1-42)-treated N9 microglia. Further, Morris water maze (MWM) testing data indicated that LPS administration acutely aggravated cognitive impairment in APP/PS1 mice, suggesting that the addition of systemic inflammation can potentially accelerate the progression of AD. Collectively, we conclude that an imbalance of TLR4/TREM2 may be a potential link between AD and systemic inflammation. TREM2 can serve as a potential therapeutic target for treating systemic inflammation in AD progression.
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“Furthermore, mounting evidence suggests that systemic inflammatory signals can be transmitted to the CNS, where they may directly impact AD pathogenesis.12–14”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [12]
In the citing paper
“This finding is consistent with previous studies showing that LPS/IFNγ stimulation down-regulated Trem2 expression via TLR4 receptors in cell lines and primary cultures of microglia/macrophages and also in mouse brains (14,16,42,88,89).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [89]
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McQuade, A., Kang, Y. J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., Shabestari, S. K., Chadarevian, J. P., Fote, G., Tu, C. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19227-5 · Cited by 361
The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology
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Metadata
- Authors
- Zhou, J., Yu, W., Zhang, M., Tian, X., Li, Y., & Lü, Y.
- Affiliations
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Chongqing Medical University (CN)
- Corresponding author
- Lü, Yang
- Venue
- Neurochemical Research
- Published
- 2019-02-12
- Volume
- 44
- Issue
- 5
- Pages
- 1138-1151
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- OpenAlex
- W2913512944
- Cited by
- 139
- References
- 78
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 17 · 2023: 15 · 2022: 28 · 2021: 30 · 2020: 16 · 2019: 2
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Alzheimer's disease, systemic inflammation, microglia, TLR4, TREM2, lipopolysaccharide, APP/PS1 mice, microglial activation, neuronal apoptosis, amyloid-beta 42, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Inflammation, Lipopolysaccharides, Male, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Toll-Like Receptor 4
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