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Research Articles, Neurobiology of Disease

Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation

Jack Rivers-Auty, Victor S. Tapia, Claire S. White, Michael J.D. Daniels, Samuel Drinkall, Paul T. Kennedy, Harry G. Spence, Shi Yu, Jack P. Green, Christopher Hoyle, James Cook, Amy Bradley, Alison E. Mather, Ruth Peters, Te-Chen Tzeng, Margaret J. Gordon, John H. Beattie, David Brough and Catherine B. Lawrence
Journal of Neuroscience 31 March 2021, 41 (13) 3025-3038; https://doi.org/10.1523/JNEUROSCI.1980-20.2020
Jack Rivers-Auty
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
3Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia
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Victor S. Tapia
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Claire S. White
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Michael J.D. Daniels
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Samuel Drinkall
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Paul T. Kennedy
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Harry G. Spence
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Shi Yu
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Jack P. Green
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Christopher Hoyle
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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James Cook
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Amy Bradley
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Alison E. Mather
4Quadram Institute Bioscience, Norwich NR4 7UA, United Kingdom
5University of East Anglia, Norwich NR4 7TJ, United Kingdom
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Ruth Peters
6School of Psychology, University of New South Wales, Sydney, New South Wales 2052, Australia
7Neuroscience Research Australia, Sydney, New South Wales 2031, Australia
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Te-Chen Tzeng
8Immunology and Inflammation, Bristol-Myers Squibb (Celgene Corporation), Cambridge, Massachusetts 02140
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Margaret J. Gordon
9Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom
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John H. Beattie
9Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom
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David Brough
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Catherine B. Lawrence
1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom
2Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, United Kingdom
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Abstract

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid β plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.

SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

  • Alzheimer's disease
  • APP/PS1
  • inflammation
  • microglia
  • NLRP3
  • zinc

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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The Journal of Neuroscience: 41 (13)
Journal of Neuroscience
Vol. 41, Issue 13
31 Mar 2021
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Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation
Jack Rivers-Auty, Victor S. Tapia, Claire S. White, Michael J.D. Daniels, Samuel Drinkall, Paul T. Kennedy, Harry G. Spence, Shi Yu, Jack P. Green, Christopher Hoyle, James Cook, Amy Bradley, Alison E. Mather, Ruth Peters, Te-Chen Tzeng, Margaret J. Gordon, John H. Beattie, David Brough, Catherine B. Lawrence
Journal of Neuroscience 31 March 2021, 41 (13) 3025-3038; DOI: 10.1523/JNEUROSCI.1980-20.2020

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Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation
Jack Rivers-Auty, Victor S. Tapia, Claire S. White, Michael J.D. Daniels, Samuel Drinkall, Paul T. Kennedy, Harry G. Spence, Shi Yu, Jack P. Green, Christopher Hoyle, James Cook, Amy Bradley, Alison E. Mather, Ruth Peters, Te-Chen Tzeng, Margaret J. Gordon, John H. Beattie, David Brough, Catherine B. Lawrence
Journal of Neuroscience 31 March 2021, 41 (13) 3025-3038; DOI: 10.1523/JNEUROSCI.1980-20.2020
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Keywords

  • Alzheimer's disease
  • APP/PS1
  • inflammation
  • microglia
  • NLRP3
  • zinc

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