TY - JOUR
T1 - Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration
AU - Acx, Hermien
AU - Serneels, Lutgarde
AU - Radaelli, Enrico
AU - Muyldermans, Serge
AU - Vincke, Cécile
AU - Pepermans, Elise
AU - Müller, Ulrike
AU - Chávez-Gutiérrez, Lucía
AU - De Strooper, Bart
N1 - © 2017 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Aph1 subunit
KW - selective inhibition
KW - side effects
KW - γ-Secretase
UR - http://www.scopus.com/inward/record.url?scp=85020198836&partnerID=8YFLogxK
U2 - 10.15252/emmm.201707561
DO - 10.15252/emmm.201707561
M3 - Article
C2 - 28588032
VL - 9
SP - 1088
EP - 1099
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 8
ER -