Acx, H;
Serneels, L;
Radaelli, E;
Muyldermans, S;
Vincke, C;
Pepermans, E;
Müller, U;
... De Strooper, B; + view all
(2017)
Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration.
EMBO Molecular Medicine
, 9
pp. 1088-1099.
10.15252/emmm.201707561.
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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.
| Type: | Article |
|---|---|
| Title: | Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.201707561 |
| Publisher version: | http://dx.doi.org/10.15252/emmm.201707561 |
| Language: | English |
| Additional information: | Copyright © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Alzheimer's disease, Aph1 subunit, selective inhibition, side effects, γ‐Secretase |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1562082 |
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