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) 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

SUBMITTER: Acx H 

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

REPOSITORIES: biostudies-literature