Successive tripeptide release and Aβ production

Satoru Funamoto, Mako Takami

Dept. Neuropathology, Fac. BioMedical Sci.

γ-Secretase cleaves βCTF at the membrane-cytoplasm boundary (ε-cleavage), to produce AICD49-99 and AICD50-99. Long Aβ species, Aβ48 and Aβ49, are produced as counterparts of AICD49-99 and AICD50-99, respectively. This indicates that ε-cleavage precedes γ-cleavage to produce Aβ. However, it has been unclear how those long Aβ species were converted into Aβ40 and Aβ42. We hypothesized that γ-secretase processed Aβ48 and Aβ49 further by releasing three residues at each step to produce Aβ42 and Aβ40, respectively. To test this hypothesis, we used LC-tandem mass spectrometry to quantify the tripeptides that were postulated to be released. We confirmed that Aβ49 was converted into Aβ40 by successively releasing two or three tripeptides and that Aβ48 was converted into Aβ42 successively releasing two tripeptides. These results strongly suggest that Aβ is generated through the stepwise processing of βCTF by γ-secretase.

Address correspondent to Dr. Satoru Funamoto, Dept. Neuropathology, Fac. BioMedical Sci., Doshisha Univ.(Kyotanabe, Kyoto 610-0394, Japan)