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International Journal of Alzheimer’s Disease
Volume 2012, Article ID 591392, 7 pages
Review Article

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

1Department of Neuropathology, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0934, Japan
2Pharma Eight Co. Ltd., Kyoto, Kyoto 602-0841, Japan

Received 13 September 2012; Revised 27 November 2012; Accepted 12 December 2012

Academic Editor: Jeremy Toyn

Copyright © 2012 Mako Takami and Satoru Funamoto. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.