Imbalance of microglial TLR4/TREM2 in LPS-treated APP/PS1 transgenic mice: a potential Link between Alzheimer's disease and systemic inflammation

Zhou, Jian; Yu, Weihua; Zhang, Man; Tian, Xin; Li, Yu; Lü, Yang

doi:10.1007/s11064-019-02748-x

Cited by 140Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Imbalance of microglial TLR4/TREM2 in LPS-treated APP/PS1 transgenic mice: a potential Link between Alzheimer's disease and systemic inflammation

Zhou, Jian, Yu, Weihua, Zhang, Man, Tian, Xin, Li, Yu, Lü, Yang·2019·Neurochemical Research

DOI 10.1007/s11064-019-02748-x

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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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Systemic inflammatory signals can be transmitted to the CNS, where they may directly impact AD pathogenesis.
“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]
LPS/IFNγ stimulation down-regulated Trem2 expression via TLR4 receptors in cell lines and primary cultures of microglia/macrophages and also in mouse brains.
“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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Curcumin Inhibits LPS-Induced Neuroinflammation by Promoting Microglial M2 Polarization via TREM2/TLR4/NF-Κb Pathways in BV2 Cells
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Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice
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The endotoxin hypothesis of Alzheimer’s disease
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TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
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TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson’s Disease Mice and LPS-Induced BV2 Cells
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The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties
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Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer’s Disease
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Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
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Recent developments in the probiotics as live biotherapeutic products (LBPs) as modulators of gut brain axis related neurological conditions
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Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models
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Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2
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Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology
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Oxymatrine inhibits neuroinflammation by Regulating M1/M2 polarization in N9 microglia through the TLR4/NF-κB pathway
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Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
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Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer’s disease
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Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer’s Disease
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TREM2 Overexpression Attenuates Cognitive Deficits in Experimental Models of Vascular Dementia
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HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis
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Alzheimer’s disease pathogenesis: standing at the crossroad of lipid metabolism and immune response
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Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease
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TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway
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Elevated amyloidoses of human IAPP and amyloid beta by lipopolysaccharide and their mitigation by carbon quantum dots
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Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation
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TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway
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Ginsenoside Rg1 alleviates lipopolysaccharide‑induced neuronal damage by inhibiting NLRP1 inflammasomes in HT22 cells
Zhang, Y., Ding, S., Chen, Y., Sun, Z., Zhang, J., Han, Y., Dong, X., Fang, Z., & Li, W. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10214 · Cited by 38 · see citing works
TREM2 improves neurological dysfunction and attenuates neuroinflammation, TLR signaling and neuronal apoptosis in the acute phase of intracerebral hemorrhage
Liu, S., Cao, X., Wu, Z., Deng, S., Fu, H., Wang, Y., & Liu, F. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.967825 · Cited by 37 · see citing works
Hydroxysafflor Yellow A Inhibits Aβ1–42-Induced Neuroinflammation by Modulating the Phenotypic Transformation of Microglia via TREM2/TLR4/NF-κB Pathway in BV-2 Cells
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Harpagide alleviate neuronal apoptosis and blood-brain barrier leakage by inhibiting TLR4/MyD88/NF-κB signaling pathway in Angiotensin II-induced microglial activation in vitro
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TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy
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The Wheel of p53 Helps to Drive the Immune System
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A natural small molecule aspidosperma-type alkaloid, hecubine, as a new TREM2 activator for alleviating lipopolysaccharide-induced neuroinflammation in vitro and in vivo
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Microbiota‐Host Immunity Communication in Neurodegenerative Disorders: Bioengineering Challenges for In Vitro Modeling
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Functionalized Cerium Dioxide Nanoparticles with Antioxidative Neuroprotection for Alzheimer’s Disease
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TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage
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SOCE-mediated NFAT1–NOX2–NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and Aβ generation
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Neuregulin-1 regulates the conversion of M1/M2 microglia phenotype via ErbB4-dependent inhibition of the NF-κB pathway
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Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer’s disease
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EVOO Polyphenols Exert Anti-Inflammatory Effects on the Microglia Cell through TREM2 Signaling Pathway
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Non-canonical pathways associated to Amyloid beta and tau protein dyshomeostasis in Alzheimer’s disease: A narrative review
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TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice
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MicroRNA‐7 negatively regulates Toll‐like receptor 4 signaling pathway through FAM177A
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Exploring microglia and their phenomenal concatenation of stress responses in neurodegenerative disorders
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Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases
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Nutrition in Alzheimer’s disease: a review of an underappreciated pathophysiological mechanism
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Jiedu Yizhi Formula Improves Cognitive Function by Regulating the Gut Dysbiosis and TLR4/NF-κB Signaling Pathway
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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
ORCID: Zhou, Jian
Yu, Weihua
Zhang, Man
Tian, Xin
Li, Yu
Lü, Yang
Venue: Neurochemical Research
Publisher: Springer Science and Business Media LLC
Published: 2019-02-12
Volume: 44
Issue: 5
Pages: 1138-1151
ISSN: 0364-3190 (ISSN-L)
1573-6903
DOI: 10.1007/s11064-019-02748-x
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
Health Sciences › Medicine › Physiology › 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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Imbalance of microglial TLR4/TREM2 in LPS-treated APP/PS1 transgenic mice: a potential Link between Alzheimer's disease and systemic inflammation

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