Abeta 11-40/42 production without gamma-secretase epsilon-site cleavage

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