Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration.

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 () subunits (). The mice show progressive cortical atrophy, neuronal loss, and gliosis.

Signature amyloid β profiles are produced by different γ-secretase complexes.

γ-Secretase complexes are involved in the generation of amyloid-β (Aβ) in the brain. Therefore, γ-secretase has been proposed as a potential therapeutic target in Alzheimer disease (AD). Targeting γ-secretase activity in AD requires the pharmacological dissociation of the processing of physiological relevant substrates and the generation of "toxic" Aβ.