Haass also presented data demonstrating that Notch and CD44 are cleaved in a PS-dependent manner at a γ-site in the middle of the transmembrane domain at a position equivalent to cleavage after residue 40 of the A β sequence. This cleavage, which he termed site 4 (S4), gives rise to a p3-like, soluble peptide of both Notch and CD44. In addition, he also reported on the well-characterized site 3 (S3) cleavage of Notch detecting a secreted peptide Mass ~4358 consistent with proteolysis just 3 amino acid residues into the transmembrane sequence.

Finally, Haass reviewed data that AβPP was cleaved at a position similar to the Notch S3, aka the ε site, and that familial Alzheimer's disease mutations in PS cause an increase in γ-cleaved APP and Notch and a decrease in ε cleavage. This latter point was corroborated by another speaker, Peter St. George-Hyslop and further suggests that increased production of Aβ is the initiating event in AD pathogenesis as opposed to transcriptional deregulation mediated by an increase in functional AICD generation.

From the data presented it is not possible to determine whether cleavage at the γ and ε sites occur sequentially or simultaneously. In addition to the products discussed above, APPC59, AAβ49 and the 9 amino acid peptide spanning the γ and ε cleavage sites have yet to be detected. Only when these fragments and their temporal production is uncovered will it be possible to determine the order of the γ and ε cleavages.—Dominic Walsh.