γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production.
γ-Secretase cleaves the carboxyl-terminal fragment (βCTF) 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 (Aβ) and the APP intracellular domain (AICD), respectively. The AICD49-99 and AICD50-99 species were identified as counterparts of the long Aβ species Aβ48 and Aβ49, respectively. We found that Aβ40 and AICD50-99 were the predominant species in cells expressing wild-type APP and presenilin, whereas the production of Aβ42 and AICD49-99 was enhanced in cells expressing familial Alzheimer's disease mutants of APP and presenilin. These long Aβ species were identified in cell lysates and mouse brain extracts, which suggests that ε-cleavage is the first cleavage of βCTF to produce Aβ 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.
Department of Neuropathology, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0934, Japan ; Pharma Eight Co. Ltd., Kyoto, Kyoto 602-0841, Japan.
Mako
M
Takami
Satoru
S
Funamoto