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Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice

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Abstract

Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe−/−, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice. These changes were associated with an increase in NADPH oxidase 2 (NOX2) expression, an important regulator of both oxidative stress and inflammatory cytokines. Furthermore, immunohistochemical analysis revealed that NOX2 was abundantly expressed in activated M1 microglia. The JAK2/STAT3 signaling pathway, an upstream regulator of NOX2, was increased in WT mice and activated to an even greater extent in Apoe−/− mice; whereas, the JAK2-specific inhibitor, AG490, reduced NOX2 expression, oxidative stress, and inflammation in Apoe-deficient mice. Also, apoE-mimetic peptide COG1410 suppressed the JAK2/STAT3 signaling pathway and significantly reduced M1 microglia activation with subsequent attenuation of oxidative stress and inflammation after SAH. Taken together, apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence through the attenuation of the JAK2/STAT3/NOX2 signaling pathway axis.

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Acknowledgments

We thank radiologist Yu Guo and his team for the help of MRI scanning and data analysis. We also thank Cognosci Inc. for the kindness of providing ApoE mimetic peptide COG1410 and Prof. David Brody for the help with improving the quality of our manuscript.

Funding

This study was funded by grants from the National Natural Science Foundation of China (81771278, 81801176), Sichuan Provincial Health and Family Planning Commission research project (17PJ076), Technology Innovation Talent Project of Sichuan Province (2018RZ0090)), Luzhou Government-Southwest Medical University Strategic Cooperation Project (2016LZXNYD-J12, 2016LZXNYD-Z02), and the Youth Innovation Project of Sichuan Medical Scientific Research (Q17082).

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Authors and Affiliations

  1. Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, No 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan Province, China

    Jinwei Pang, Jianhua Peng, Ping Yang, Li Kuai, Ligang Chen & Yong Jiang

  2. Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA

    Nathanael Matei & John H. Zhang

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

    Yue Wu & Xiaochuan Sun

  4. Duke University Medical Center, Durham, North Carolina, USA

    Michael P. Vitek

  5. Cognosci Inc., Research Triangle Park, North Carolina, USA

    Michael P. Vitek & Fengqiao Li

  6. Sichuan Province Neurosurgery Clinical Medical Research Center, Luzhou, China

    Yong Jiang

  7. Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China

    Yong Jiang

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  1. Jinwei Pang
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All experimental procedures were approved by the Ethics Committee of Southwest Medical University and carried out in accordance with Stroke Treatment and Academic Roundtable (STAIR) guidelines and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Pang, J., Peng, J., Matei, N. et al. Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice. Transl. Stroke Res. 9, 654–668 (2018). https://doi.org/10.1007/s12975-018-0665-4

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