γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloidβ-Protein Production

γ -Secretase cleaves the carboxyl-terminal fragment ( β CTF) of APP not only in the middle of the transmembrane domain ( γ -cleavage), but also at sites close to the membrane/cytoplasm boundary ( ε -cleavage), to produce the amyloid β protein (A β ) and the APP intracellular domain (AICD), respectively. The AICD49–99 and AICD50–99 species were identified as counterparts of the long A β species A β 48 and A β 49, respectively. We found that A β 40 and AICD50–99 were the predominant species in cells expressing wild-type APP and presenilin, whereas the production of A β 42 and AICD49–99 was enhanced in cells expressing familial Alzheimer's disease mutants of APP and presenilin. These long A β species were identified in cell lysates and mouse brain extracts, which suggests that ε -cleavage is the first cleavage of β CTF to produce A β by γ -secretase. Here, we review the progress of research on the mechanism underlying the proteolysis of the APP transmembrane domain based on tri- and tetrapeptide release.