If you came to Amsterdam hoping to hear a lot of new data on Aβ peptide inhibitors, you might have learned more by window shopping in the red-light district. This doesn't mean that the session was without merit. Barbara Cordell (Abstract 937) gave an excellent presentation on issues surrounding our understanding of c-secretase(s). Previous reports of a compound that inhibits the production of Aβ40 but not Aβ42 have been interpreted as supporting the existence of more than one C-secretase. However, Cordell noted that in these experiments, the decrease in Aβ40 is accompanied by an increase in Aβ42. She suggested that the compound is not a specific C-secretase inhibitor but rather an inhibitor of a carboxy-terminal exopeptidase, which is responsible for converting long Aβ to shorter forms.

Cordell also pointed out that the "theoretical" transmembrane domain of Aβ is precisely that: "theoretical." For Aβ, it is possible the cleavage occurs outside the membrane, because we really don't know where Aβ sits. Further supporting her hypothesis is the fact that one rarely sees Aβ peptides shorter than 39 amino acids. Because carboxy-terminal exopeptidases "don't like to chew glycines," Cordell proposed, they stop before a.a. 37 and 38.

Dennis Selkoe (Abstract 940) summarized his work on Aβ processing, emphasizing that all known PS1 and PS2 mutations increase Aβ42. He also suggested that the fact that PS mutations influence Aβ40 to Aβ42 ratios in non-neuronal cells from a variety of peripheral systems and cause rapid stabilization of oligomeric forms of Aβ further supports the Amyloid Casade Hypothesis. If it happens in systems so far removed from brain, and it happens in neuronal systems too, it is most likely a central process. In response to Cordell's suggestion that the c-secretase does not need to cleave Aβ within the membrane, Selkoe favored the hypothesis that c-secretase binds with normal presenilin so that it can cleave APP within the membrane.—Brian Cummings

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