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

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Rivers-Auty, J ORCID: 0000-0001-5321-2347, Tapia, VS, White, CS, Daniels, MJD, Drinkall, S, Kennedy, PT, Spence, HG, Yu, S, Green, JP, Hoyle, C, Cook, J, Bradley, A, Mather, AE, Peters, R, Tzeng, TC, Gordon, MJ, Beattie, JH, Brough, D and Lawrence, CB 2021 , 'Zinc status alters Alzheimer's disease progression through NLRP3-dependent inflammation' , Journal of Neuroscience, vol. 41, no. 13 , pp. 3025-3038 , doi: 10.1523/JNEUROSCI.1980-20.2020.

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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 (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.

Item Type: Article
Authors/Creators:Rivers-Auty, J and Tapia, VS and White, CS and Daniels, MJD and Drinkall, S and Kennedy, PT and Spence, HG and Yu, S and Green, JP and Hoyle, C and Cook, J and Bradley, A and Mather, AE and Peters, R and Tzeng, TC and Gordon, MJ and Beattie, JH and Brough, D and Lawrence, CB
Keywords: APP/PS1, Alzheimer's disease, NLRP3, inflammation, microglia, zinc
Journal or Publication Title: Journal of Neuroscience
Publisher: Society for Neuroscience
ISSN: 0270-6474
DOI / ID Number: 10.1523/JNEUROSCI.1980-20.2020
Copyright Information:

Copyright © 2021 Rivers-Auty et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license, (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution and reprodution in any medium provided that the original work is properly attributed.

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