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Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease

Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microg...

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Autores principales: Lau, Shun-Fat, Fu, Amy K. Y., Ip, Nancy Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195901/
https://www.ncbi.nlm.nih.gov/pubmed/33847763
http://dx.doi.org/10.1007/s00018-021-03810-0
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author Lau, Shun-Fat
Fu, Amy K. Y.
Ip, Nancy Y.
author_facet Lau, Shun-Fat
Fu, Amy K. Y.
Ip, Nancy Y.
author_sort Lau, Shun-Fat
collection PubMed
description Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome–IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.
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spelling pubmed-81959012021-06-28 Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease Lau, Shun-Fat Fu, Amy K. Y. Ip, Nancy Y. Cell Mol Life Sci Review Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome–IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development. Springer International Publishing 2021-04-13 2021 /pmc/articles/PMC8195901/ /pubmed/33847763 http://dx.doi.org/10.1007/s00018-021-03810-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review
Lau, Shun-Fat
Fu, Amy K. Y.
Ip, Nancy Y.
Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title_full Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title_fullStr Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title_full_unstemmed Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title_short Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
title_sort cytokine signaling convergence regulates the microglial state transition in alzheimer’s disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195901/
https://www.ncbi.nlm.nih.gov/pubmed/33847763
http://dx.doi.org/10.1007/s00018-021-03810-0
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