| First Author | Acx H | Year | 2017 |
| Journal | EMBO Mol Med | Volume | 9 |
| Issue | 8 | Pages | 1088-1099 |
| PubMed ID | 28588032 | Mgi Jnum | J:262463 |
| Mgi Id | MGI:6161865 | Doi | 10.15252/emmm.201707561 |
| Citation | Acx H, et al. (2017) Inactivation of gamma-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration. EMBO Mol Med 9(8):1088-1099 |
| abstractText | gamma-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all gamma-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 gamma-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-gamma-secretase inhibitors should be considered for treatment of Alzheimer's disease. |
