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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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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 Aβ1−42. Similar alterations were observed in our in vitro experiment with β-amyloid1–42 (Aβ1–42)-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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Acknowledgements

We would like to thank AJE (http://www.aje.com/) for English language editing and proofreading this manuscript. This work was supported by Grants from the Chongqing Natural Science Foundation (cstc2018jcyjAX0169), the National Natural Science Foundation of China (81671286, 31570826), the National Key Clinical Specialties Construction Program of China (No. [2013]544), and the Application Program of the Chongqing Science & Technology Commission (cstc2014yykfA110002).

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  1. Jian Zhou, Weihua Yu and Man Zhang contributed equally to this work.

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  1. Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, China

    Jian Zhou, Weihua Yu, Man Zhang & Yang Lü

  2. Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, China

    Jian Zhou & Weihua Yu

  3. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Xin Tian

  4. Department of Pathology, Chongqing Medical University, Chongqing, 400016, China

    Yu Li

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Supplementary material 1 Supplementary Figure S1. Localization analysis for TREM2 (green) and TLR4 (red) in the cortex of WT mice using immunofluorescence double-labeling. TREM2 and TLR4 were expressed on the surface of microglia. Scale bar: 20 μm. Supplementary Figure S2. Detailed comparison of the escape latency on the navigation test on days 1, 2, 3, 4, 5 and 7. *Significant compared with the WT group (p < 0.05); #Significant compared with the APP/PS1 group (p < 0.05); ▲Significant compared with the WT+LPS group (p < 0.05). (PDF 209 KB)

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Zhou, J., Yu, W., Zhang, M. et al. Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer’s Disease and Systemic Inflammation. Neurochem Res 44, 1138–1151 (2019). https://doi.org/10.1007/s11064-019-02748-x

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