Dataset Information

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

ABSTRACT: ?-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all ?-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 ?-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-?-secretase inhibitors should be considered for treatment of Alzheimer's disease.

SUBMITTER: Acx H

PROVIDER: S-EPMC5538297 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Acx Hermien H Serneels Lutgarde L Radaelli Enrico E Muyldermans Serge S Vincke Cécile C Pepermans Elise E Müller Ulrike U Chávez-Gutiérrez Lucía L De Strooper Bart B

EMBO molecular medicine 20170801 8

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 ...[more]

PMID: 28588032

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

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

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