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Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model

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Abstract

Clearance of amyloid-beta (Aβ) from the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Current studies mainly focus on the central approach of Aβ clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aβ, suggesting that the peripheral approach of removing Aβ from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aβ burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aβ concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aβ in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aβ burden and other AD-type pathologies were measured after 1 month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aβ levels in both CKD patients and APP/PS1 mice. Aβ levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aβ in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aβ deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APPswe/PS1 mice. Importantly, the Aβ phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aβ clearance using a peripheral approach could be a desirable therapeutic strategy for AD.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (Grant Number 81471296 and 81625007). W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease.

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Authors and Affiliations

  1. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China

    Wang-Sheng Jin, Lin-Lin Shen, Xian-Le Bu, Si-Han Chen, Chang-Yue Gao, Hua-Dong Zhou & Yan-Jiang Wang

  2. Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China

    Wei-Wei Zhang & Ya-Ni He

  3. Ministry of Education Key Laboratory of Child Development and Disorders and 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 & Zhifang Dong

  4. Department of Physiology, Third Military Medical University, Chongqing, China

    Jia-Xiang Xiong & Zhi-An Hu

  5. Townsend Family Laboratories, Department of Psychiatry, Center for Brain Health, The University of British Columbia, Vancouver, BC, V6T1Z3, Canada

    Weihong Song

  6. School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, Australia

    Xin-Fu Zhou

  7. Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Science, Shanghai, China

    Yi-Zheng Wang

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  1. Wang-Sheng Jin
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Correspondence to Yan-Jiang Wang.

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Jin, WS., Shen, LL., Bu, XL. et al. Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol 134, 207–220 (2017). https://doi.org/10.1007/s00401-017-1721-y

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