Background: ␥-Secretase complexes generate amyloid-␤ (A␤) in Alzheimer disease. Results: A␤ profiles of the four ␥-secretase complexes expressed in humans show that PSEN regulates total peptide levels and the A␤ 38 pathway, whereas APH1 affects mainly the efficiency of the carboxypeptidase-like activity. Conclusion: ␥-Secretase subunit composition regulates A␤ generation. Significance: These intrinsic differences could be used to advance AD therapeutic development.

Abstractγ‐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.