Secretion of long Aβ-related peptides processed at ε-cleavage site is dependent on the α-secretase pre-cutting

AbstractAβ is the major component of amyloid in the brain in Alzheimer's disease and is derived from Alzheimer amyloid precursor protein (APP) by sequential proteolytic cleavage involving α-, 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). However, the precise relationship between γ- and ε-cleavage is still unknown. In this paper, I analyzed Aβ-related peptides using immunoprecipitation and liquid chromatography ion trap mass spectrometer and found some long Aβ-related peptides, starting at Aβ residues 16Lys–23Asp and ending at 43Thr–52Leu, in the culture media of COS-1 cells and in human brain extract. These results indicated that longer Aβ-related peptides cleaved at ε-cleavage site were secreted under normal conditions and were dependent on the α-secretase cleavage products