Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration.
EMBO Mol Med
; 9(8): 1088-1099, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28588032
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.
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MEDLINE
Assunto principal:
Endopeptidases
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Prosencéfalo
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Doenças Neurodegenerativas
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article