Journal
JOURNAL OF NEUROSCIENCE
Volume 41, Issue 13, Pages -Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1980-20.2020
Keywords
Alzheimer's disease; APP/PS1; inflammation; microglia; NLRP3; zinc
Categories
Funding
- ADNI National Institutes of Health [U01 AG024904]
- ADNI Department of Defense Award [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- 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
- 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
- Transition Therapeutics
- Canadian Institutes of Health Research
- Biotechnology and Biological Sciences Research Council Institute Strategic Program Microbes in the Food Chain [BB/R012504/1, BBS/E/F/000PR10348, BBS/E/F/000PR10351]
- Biotechnology and Biological Sciences Research Council fellowship grant [BB/P01061X/1]
- Alzheimer Society Project Grant [AS-PG-2013-007]
- University of Manchester Strategic Fund
- BBSRC [BBS/E/F/000PR10348, BBS/E/F/000PR10351] Funding Source: UKRI
- MRC [1793347] Funding Source: UKRI
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Alzheimer's disease is a devastating neurodegenerative disease with increasing prevalence, and inflammatory lifestyle factors may increase the risk. Zinc deficiency, the most prevalent malnutrition globally, could be a risk factor for Alzheimer's disease, while zinc supplementation may reduce the risk of cognitive decline.
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 b 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.
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