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NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease

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Abstract

The activation of the NLRP3 inflammasome signaling pathway plays an important role in the neuroinflammation in Alzheimer’s disease (AD). In this study, we investigated the effects of JC-124, a rationally designed NLRP3 inflammasome inhibitor, on AD-related deficits in CRND8 APP transgenic mice (TgCRND8). We first demonstrated increased formation and activation of NLRP3 inflammasome in TgCRND8 mice compared to non-transgenic littermate controls, which was inhibited by the treatment with JC-124. Importantly, JC-124 treatment led to decreased levels of Aβ deposition and decreased levels of soluble and insoluble Aβ1–42 in the brain of CRND8 mice which was accompanied by reduced β-cleavage of APP, reduced activation of microglia but enhanced astrocytosis. Oxidative stress was decreased and synaptophysin was increased in the CRND8 mice after JC-124 treatment, demonstrating a neuroprotective effect. Overall, these data demonstrated beneficial effects of JC-124 as a specific NLRP3 inflammasome inhibitor in AD mouse model and supported the further development of NLRP3 inflammasome inhibitors as a viable option for AD therapeutics.

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Acknowledgements

The work was supported in part by the National Institute on Aging of the National Institutes of Health [R01NS083385 and RFAG049479 to X.Z. and R01AG041161 to S.Z.]; Alzheimer’s Association [AARG-16-443584 to X.Z.]; Dr. Robert M. Kohrman Memorial Fund to X.Z., Alzheimer’s Drug Discovery Foundation [20150601 to S.Z.]; and the National Natural Sciences Foundation of China [81100594 to J.Y.].

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Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China

    Jun Yin

  2. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Jun Yin, Fanpeng Zhao & Xiongwei Zhu

  3. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Jeremy E. Chojnacki, Jacob Fulp & Shijun Zhang

  4. Department of Neurobiology, Northwestern University, Evanston, IL, USA

    William L. Klein

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  1. Jun Yin
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Correspondence to Shijun Zhang or Xiongwei Zhu.

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Yin, J., Zhao, F., Chojnacki, J.E. et al. NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 55, 1977–1987 (2018). https://doi.org/10.1007/s12035-017-0467-9

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  • DOI: https://doi.org/10.1007/s12035-017-0467-9

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