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Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease

Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genet...

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Autores principales: Tan, M-S, Tan, L, Jiang, T, Zhu, X-C, Wang, H-F, Jia, C-D, Yu, J-T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454321/
https://www.ncbi.nlm.nih.gov/pubmed/25144717
http://dx.doi.org/10.1038/cddis.2014.348
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author Tan, M-S
Tan, L
Jiang, T
Zhu, X-C
Wang, H-F
Jia, C-D
Yu, J-T
author_facet Tan, M-S
Tan, L
Jiang, T
Zhu, X-C
Wang, H-F
Jia, C-D
Yu, J-T
author_sort Tan, M-S
collection PubMed
description Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1-mediated caspase-1-dependent ‘pyroptosis' in cultured cortical neurons in response to amyloid-β. Moreover, we employed direct in vivo infusion of non-viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy.
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spelling pubmed-44543212015-06-15 Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease Tan, M-S Tan, L Jiang, T Zhu, X-C Wang, H-F Jia, C-D Yu, J-T Cell Death Dis Original Article Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1-mediated caspase-1-dependent ‘pyroptosis' in cultured cortical neurons in response to amyloid-β. Moreover, we employed direct in vivo infusion of non-viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy. Nature Publishing Group 2014-08 2014-08-21 /pmc/articles/PMC4454321/ /pubmed/25144717 http://dx.doi.org/10.1038/cddis.2014.348 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Tan, M-S
Tan, L
Jiang, T
Zhu, X-C
Wang, H-F
Jia, C-D
Yu, J-T
Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title_full Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title_fullStr Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title_full_unstemmed Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title_short Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease
title_sort amyloid-β induces nlrp1-dependent neuronal pyroptosis in models of alzheimer's disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454321/
https://www.ncbi.nlm.nih.gov/pubmed/25144717
http://dx.doi.org/10.1038/cddis.2014.348
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