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PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through acti...

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Autores principales: Tible, Marion, Mouton Liger, François, Schmitt, Julien, Giralt, Albert, Farid, Karim, Thomasseau, Sylvie, Gourmaud, Sarah, Paquet, Claire, Rondi Reig, Laure, Meurs, Eliane, Girault, Jean‐Antoine, Hugon, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516179/
https://www.ncbi.nlm.nih.gov/pubmed/30821420
http://dx.doi.org/10.1111/acel.12887
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author Tible, Marion
Mouton Liger, François
Schmitt, Julien
Giralt, Albert
Farid, Karim
Thomasseau, Sylvie
Gourmaud, Sarah
Paquet, Claire
Rondi Reig, Laure
Meurs, Eliane
Girault, Jean‐Antoine
Hugon, Jacques
author_facet Tible, Marion
Mouton Liger, François
Schmitt, Julien
Giralt, Albert
Farid, Karim
Thomasseau, Sylvie
Gourmaud, Sarah
Paquet, Claire
Rondi Reig, Laure
Meurs, Eliane
Girault, Jean‐Antoine
Hugon, Jacques
author_sort Tible, Marion
collection PubMed
description Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.
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spelling pubmed-65161792019-06-01 PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions Tible, Marion Mouton Liger, François Schmitt, Julien Giralt, Albert Farid, Karim Thomasseau, Sylvie Gourmaud, Sarah Paquet, Claire Rondi Reig, Laure Meurs, Eliane Girault, Jean‐Antoine Hugon, Jacques Aging Cell Original Articles Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD. John Wiley and Sons Inc. 2019-03-01 2019-06 /pmc/articles/PMC6516179/ /pubmed/30821420 http://dx.doi.org/10.1111/acel.12887 Text en © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Tible, Marion
Mouton Liger, François
Schmitt, Julien
Giralt, Albert
Farid, Karim
Thomasseau, Sylvie
Gourmaud, Sarah
Paquet, Claire
Rondi Reig, Laure
Meurs, Eliane
Girault, Jean‐Antoine
Hugon, Jacques
PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title_full PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title_fullStr PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title_full_unstemmed PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title_short PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
title_sort pkr knockout in the 5xfad model of alzheimer's disease reveals beneficial effects on spatial memory and brain lesions
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516179/
https://www.ncbi.nlm.nih.gov/pubmed/30821420
http://dx.doi.org/10.1111/acel.12887
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