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Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies

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Abstract

Accumulation of pathological tau is the hallmark of Alzheimer’s disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unknown. Here, we found that cisterna magna injected 131I-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood, and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than those in femoral artery in humans. These findings suggest that tau proteins can efflux out of the brain and be cleared in the periphery under physiological conditions. Next, we showed that lowering blood tau levels via peritoneal dialysis could reduce interstitial fluid (ISF) tau levels in the brain, and tau levels in the blood and ISF were dynamically correlated; furthermore, tau efflux from the brain was accelerated after the addition of another set of peripheral system in a parabiosis model. Finally, we established parabiosis mouse models using tau transgenic mice and their wild-type littermates and found that brain tau levels and related pathologies in parabiotic transgenic mice were significantly reduced after parabiosis, suggesting that chronic enhancement of peripheral tau clearance alleviates pathological tau accumulation and neurodegeneration in the brain. Our study provides the first evidence of physiological clearance of brain-derived pathological tau in the periphery, suggesting that enhancing peripheral tau clearance is a potential therapeutic strategy for tauopathies.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC) through Grants 81625007, 91749206, and 81600949. The authors would like to thank the following for aid in radiolabelling of 131I-tau: Professor Ding-De Huang from Department of Nuclear Medicine, Southwest Hospital of Third Military Medical University, and Professor Zhi-Ping Peng from Department of Radiological Medicine, College of Basic Medical, Chongqing Medical University. The authors would also like to thank professor Shi-Fei Tong from The Third Affiliated Hospital of Chongqing Medical University for collecting blood samples from patients.

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Authors and Affiliations

  1. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    Jun Wang, Wang-Sheng Jin, Xian-Le Bu, Fan Zeng, Wei-Wei Li, Lin-Lin Shen, Zhen-Qian Zhuang, Bin-Lu Sun, Jie Zhu, Xiu-Qing Yao, Gui-Hua Zeng, Hua-Dong Zhou, Yu-Hui Liu & Yan-Jiang Wang

  2. State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China

    Jian-Xin Jiang & Yan-Jiang Wang

  3. Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Zhi-Lin Huang & Zhi-Fang Dong

  4. Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China

    Yuqiang Fang

  5. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

    Jin-Tai Yu

  6. Department of Physiology, Collaborative Innovation Center for Brain Science, Third Military Medical University, Chongqing, China

    Zhian Hu

  7. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

    Weihong Song

  8. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Yan-Jiang Wang

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  1. Jun Wang
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Wang, J., Jin, WS., Bu, XL. et al. Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies. Acta Neuropathol 136, 525–536 (2018). https://doi.org/10.1007/s00401-018-1891-2

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