Aβ 11–40/42 production without γ-secretase ε-site cleavage

The accumulation and deposition of fibrillar Aβ is thought to be the primary cause of Alzheimer’s disease. Aβ is derived from Alzheimer amyloid precursor protein (APP) by sequential proteolytic cleavage involving β- and γ-secretase. Recently, γ-secretase was shown to cleave near the cytoplasmic membrane boundary of APP (called the ε-cleavage), as well as in the middle of the membrane domain (γ-cleavage). It has been reported that the C-terminus of Aβ is generated via a series of sequential cleavages, ε-cleavage followed by γ-cleavage. However, recent article has reported that γ- and ε-site cleavage are regulated independently. The relationship between γ-site and ε-site cleavage is still unknown. In this study, we analyzed the generation of AICD and Aβ in CHO cells expressing APP derivatives. We found that ε-site cleavage preferentially occurs α-secretase processing product, and that Aβ 11–40/42 was generated without γ-secretase ε-site cleavage, indicating that γ-site cleavage and ε-site cleavage were regulated differentially.