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Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration

γ‐Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ‐secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits...

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Autores principales: Acx, Hermien, Serneels, Lutgarde, Radaelli, Enrico, Muyldermans, Serge, Vincke, Cécile, Pepermans, Elise, Müller, Ulrike, Chávez‐Gutiérrez, Lucía, De Strooper, Bart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538297/
https://www.ncbi.nlm.nih.gov/pubmed/28588032
http://dx.doi.org/10.15252/emmm.201707561
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author Acx, Hermien
Serneels, Lutgarde
Radaelli, Enrico
Muyldermans, Serge
Vincke, Cécile
Pepermans, Elise
Müller, Ulrike
Chávez‐Gutiérrez, Lucía
De Strooper, Bart
author_facet Acx, Hermien
Serneels, Lutgarde
Radaelli, Enrico
Muyldermans, Serge
Vincke, Cécile
Pepermans, Elise
Müller, Ulrike
Chávez‐Gutiérrez, Lucía
De Strooper, Bart
author_sort Acx, Hermien
collection PubMed
description γ‐Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ‐secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre (+)). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10‐fold accumulation of membrane‐bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of γ‐secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane‐bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a‐ or Aph1bc‐secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1‐γ‐secretase inhibitors should be considered for treatment of Alzheimer's disease.
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spelling pubmed-55382972017-08-04 Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration Acx, Hermien Serneels, Lutgarde Radaelli, Enrico Muyldermans, Serge Vincke, Cécile Pepermans, Elise Müller, Ulrike Chávez‐Gutiérrez, Lucía De Strooper, Bart EMBO Mol Med Research Articles γ‐Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ‐secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre (+)). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10‐fold accumulation of membrane‐bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of γ‐secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane‐bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a‐ or Aph1bc‐secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1‐γ‐secretase inhibitors should be considered for treatment of Alzheimer's disease. John Wiley and Sons Inc. 2017-06-06 2017-08 /pmc/articles/PMC5538297/ /pubmed/28588032 http://dx.doi.org/10.15252/emmm.201707561 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (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 Research Articles
Acx, Hermien
Serneels, Lutgarde
Radaelli, Enrico
Muyldermans, Serge
Vincke, Cécile
Pepermans, Elise
Müller, Ulrike
Chávez‐Gutiérrez, Lucía
De Strooper, Bart
Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title_full Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title_fullStr Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title_full_unstemmed Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title_short Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
title_sort inactivation of γ‐secretases leads to accumulation of substrates and non‐alzheimer neurodegeneration
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538297/
https://www.ncbi.nlm.nih.gov/pubmed/28588032
http://dx.doi.org/10.15252/emmm.201707561
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