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. 2012:2012:591392.
doi: 10.1155/2012/591392. Epub 2012 Dec 31.

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

Mako Takami  1 , Satoru Funamoto
Affiliations

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

Mako Takami et al. Int J Alzheimers Dis. 2012.

Abstract

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.

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Figures

Figure 1
Figure 1
βCTF is cleaved at the membrane-cytoplasm boundary and not in the middle of the transmembrane domain (ε-cleavage), to release the AICD49–99 and AICD50–99 species. The production of AICD species was inhibited in the presence of a γ-secretase inhibitor. ε-Cleavage is analogous to the S3 cleavage of mNotch-1. Red indicates the transmembrane domain.
Figure 2
Figure 2
Relationship between γ- and ε-cleavage. (a) Cells expressing wild-type PS or APP predominantly produce Aβ40 and AICD50–99, while cells expressing a FAD mutant of PS or APP exhibited increased proportion of Aβ42 and AICD49–99. (b) Expression of Aβ49 results in an increase in Aβ40/Aβ42 ratio, whereas expression of Aβ48 leads to opposite results. ↗ increase, ↘ decrease.
Figure 3
Figure 3
Tri- and tetrapeptide release from βCTF. (a) Upon ε-cleavage at ε48, γ-secretase releases the VIT and TVI tripeptides successively to produce Aβ42. (b) In the Aβ40 product line, after ε-cleavage at ε49, βCTF is converted into Aβ40 by releasing ITL, VIV, and IAT. Aβ42 is a direct substrate during Aβ38 production, which acts by releasing the VVIA tetrapeptide.
Figure 4
Figure 4
Multiple cleavage sites on the transmembrane domain of γ-secretase substrates. APP [38], APLP-1 [30, 39], mNotch-1 [40], and CD44 [41].
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