. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.

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  1. This is an excellent study that describes missing pieces in the puzzle of γ-secretase: the existence of intervening peptides generated during the formation of Aβ and the APP intracellular domain (AICD). These peptides had been hypothesized for years but have not been observed until now. Furthermore, careful quantification using appropriate standardization was carried out, allowing rigorous and detailed kinetic analysis of the production of the resultant tri- and tetrapeptides. This study provides a linchpin to the Ihara lab's efforts over the course of several years to demonstrate that 1) epsilon cleavage of APP C99 substrate occurs first, followed by trimming every three (sometimes four) residues of initially formed long Aβ peptides, and (2) the site of initial epsilon cleavage largely determines the proportion of Aβ40 and Aβ42 that is ultimately produced, with Aβ49 being cleaved to -46, -43, and -40 and Aβ48 being cleaved to -45, -42, and -38.