γ-Secretase can cleave amyloid precursor protein fragments independent of α- and β-secretase pre-cutting

Abeta is the major component of amyloid in the brain in Alzheimer's disease and is derived from an amyloid precursor protein (APP) by the sequential proteolytic processing of two putative proteases, called beta- and gamma-secretase. To clarify the mechanism of gamma-secretase processing, we created constructs contained the C-terminal domain of APP and analyzed the processing in COS-1 cells. We found that C-terminal fragments (CTFs) containing a short extra N-terminal region before the beta-secretase cleavage site were directly processed at gamma-secretase cleavage site. This suggests that gamma-secretase cleavage occurs independently and is not dependent on alpha- and beta-secretase cleavage.