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

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. Green open access

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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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