Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
Abstract 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)...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707561 |
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| author | Hermien Acx Lutgarde Serneels Enrico Radaelli Serge Muyldermans Cécile Vincke Elise Pepermans Ulrike Müller Lucía Chávez‐Gutiérrez Bart De Strooper |
| author_facet | Hermien Acx Lutgarde Serneels Enrico Radaelli Serge Muyldermans Cécile Vincke Elise Pepermans Ulrike Müller Lucía Chávez‐Gutiérrez Bart De Strooper |
| author_sort | Hermien Acx |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-91f0316e230c40d1b68019d43f30295d |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-91f0316e230c40d1b68019d43f30295d2025-08-20T04:03:03ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-06-01981088109910.15252/emmm.201707561Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegenerationHermien Acx0Lutgarde Serneels1Enrico Radaelli2Serge Muyldermans3Cécile Vincke4Elise Pepermans5Ulrike Müller6Lucía Chávez‐Gutiérrez7Bart De Strooper8VIB Center for Brain and Disease ResearchVIB Center for Brain and Disease ResearchVIB Center for Brain and Disease ResearchCellular and Molecular Immunology, Vrije Universiteit BrusselCellular and Molecular Immunology, Vrije Universiteit BrusselVIB Center for Brain and Disease ResearchInstitute for Pharmacy and Molecular Biotechnology (IPMB), University of HeidelbergVIB Center for Brain and Disease ResearchVIB Center for Brain and Disease ResearchAbstract 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.https://doi.org/10.15252/emmm.201707561Alzheimer's diseaseAph1 subunitselective inhibitionside effectsγ‐Secretase |
| spellingShingle | Hermien Acx Lutgarde Serneels Enrico Radaelli Serge Muyldermans Cécile Vincke Elise Pepermans Ulrike Müller Lucía Chávez‐Gutiérrez Bart De Strooper Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration EMBO Molecular Medicine Alzheimer's disease Aph1 subunit selective inhibition side effects γ‐Secretase |
| 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 | Alzheimer's disease Aph1 subunit selective inhibition side effects γ‐Secretase |
| url | https://doi.org/10.15252/emmm.201707561 |
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