Zinc status alters Alzheimer's disease progression through NLRP3-dependent inflammation

Jack Rivers-Auty, Victor S Tapia, Claire S White, Michael Jd 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* (Corresponding Author), Catherine B Lawrence* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
4 Downloads (Pure)

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 (35mg/kg zinc) or diet deficient in zinc (3mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid beta (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 StatementAlzheimer'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 hypothesised 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 due to 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.

Original languageEnglish
Pages (from-to)3025-3038
Number of pages14
JournalJournal of Neuroscience
Volume41
Issue number13
Early online date17 Feb 2021
DOIs
Publication statusPublished - 31 Mar 2021

Bibliographical note

Data collection and sharing for this project were funded by ADNI National Institutes of Health Grant U01 AG024904 and ADNI Department of Defense Award W81XWH-12-2-0012. ADNI is supported by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Company, Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. A.E.M. is a Food Standards Agency Fellow and is supported by the Biotechnology and Biological Sciences Research Council Institute Strategic Program Microbes in the Food Chain BB/R012504/1 and its constituent projects BBS/E/F/000PR10348 (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain) and BBS/E/F/000PR10351 (Theme 3, Microbial Communities in the Food Chain). J.R.-A. was a Future Leader Fellow supported by the Biotechnology and Biological Sciences Research Council fellowship grant (Understanding how dietary zinc and inflammation impact healthy ageing in the brain; BB/P01061X/1). This work was also supported by Alzheimer Society Project Grant AS-PG-2013-007 to C.B.L. and D.B. that funded the salary of J.R.-A. The Histology Facility equipment that was used in this study was purchased by the University of Manchester Strategic Fund. We thank the University of Manchester Biological Services Facility and their expert animal husbandry, the Bioimaging Facility, and the Histology Facility for making this work possible.

Keywords

  • APP/PS1
  • Alzheimer's disease
  • Inflammation
  • Microglia
  • NLRP3
  • Zinc

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