Cargando…
Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging
Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a si...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486940/ https://www.ncbi.nlm.nih.gov/pubmed/32917871 http://dx.doi.org/10.1038/s41467-020-18405-9 |
_version_ | 1783581406983618560 |
---|---|
author | Flores, Joseph Noël, Anastasia Foveau, Bénédicte Beauchet, Olivier LeBlanc, Andréa C. |
author_facet | Flores, Joseph Noël, Anastasia Foveau, Bénédicte Beauchet, Olivier LeBlanc, Andréa C. |
author_sort | Flores, Joseph |
collection | PubMed |
description | Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APP(Sw/Ind)) J20 and wild-type mice with VX-765 delays both APP(Sw/Ind)- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD. |
format | Online Article Text |
id | pubmed-7486940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74869402020-09-25 Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging Flores, Joseph Noël, Anastasia Foveau, Bénédicte Beauchet, Olivier LeBlanc, Andréa C. Nat Commun Article Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APP(Sw/Ind)) J20 and wild-type mice with VX-765 delays both APP(Sw/Ind)- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD. Nature Publishing Group UK 2020-09-11 /pmc/articles/PMC7486940/ /pubmed/32917871 http://dx.doi.org/10.1038/s41467-020-18405-9 Text en © The Author(s) 2020, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Flores, Joseph Noël, Anastasia Foveau, Bénédicte Beauchet, Olivier LeBlanc, Andréa C. Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title | Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title_full | Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title_fullStr | Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title_full_unstemmed | Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title_short | Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging |
title_sort | pre-symptomatic caspase-1 inhibitor delays cognitive decline in a mouse model of alzheimer disease and aging |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486940/ https://www.ncbi.nlm.nih.gov/pubmed/32917871 http://dx.doi.org/10.1038/s41467-020-18405-9 |
work_keys_str_mv | AT floresjoseph presymptomaticcaspase1inhibitordelayscognitivedeclineinamousemodelofalzheimerdiseaseandaging AT noelanastasia presymptomaticcaspase1inhibitordelayscognitivedeclineinamousemodelofalzheimerdiseaseandaging AT foveaubenedicte presymptomaticcaspase1inhibitordelayscognitivedeclineinamousemodelofalzheimerdiseaseandaging AT beauchetolivier presymptomaticcaspase1inhibitordelayscognitivedeclineinamousemodelofalzheimerdiseaseandaging AT leblancandreac presymptomaticcaspase1inhibitordelayscognitivedeclineinamousemodelofalzheimerdiseaseandaging |