Just when it appeared as though the mechanisms of the proteolytic processing of APP were finally becoming apparent, Andreas Weidemann presented an elegant study demonstrating the existence of a different processing event (122.2). Using SH5Y and Cos-7 cells expressing C-terminally tagged APP and SPACT (C99) he isolated C-terminal fragments (CTFs) from membrane preparations and by radiosequencing demonstrated the presence of a CTF generated by cleavage between Leu645 and Val646 (APP695 numbering). Cleavage at this site (termed epsilon) appeared to occur late in the secretory pathway and was not affected by γ-secretase inhibitors and did not appear to be a precursor to γ-secretase cleavage.—Dominic Walsh

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