Progress towards the development of A-beta peptide inhibitors

by Brian Cummings

21 July 1998. If you came to Amsterdam hoping to hear a lot of new data on A-beta 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 gamma secretase(s). Previous reports of a compound that inhibits the production of A-beta40 but not A-beta42 have been interpreted as supporting the existence of more than one gamma secretase. However, Cordell noted that in these experiments, the decrease in A-beta40 is accompanied by an increase in A-beta42. She suggested that the compound is not a specific gamma secretase inhibitor but rather an inhibitor of a carboxy-terminal exopeptidase, which is responsible for converting long A-beta to shorter forms.

Cordell also pointed out that the "theoretical" transmembrane domain of A-beta is precisely that: "theoretical". For A-beta, it is possible the cleavage occurs outside the membrane, because we really don't know where A-beta sits. Further supporting her hypothesis is the fact that one rarely sees A-beta 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 A-beta processing, emphasizing that all known PS1 and PS2 mutations increase A-beta42. He also suggested that the fact that PS mutations influence A-beta40 to A-beta42 ratios in non-neuronal cells from a variety of peripheral systems and cause rapid stabilization of oligomeric forms of A-beta 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 gamma secretase does not need to cleave A-beta within the membrane, Selkoe favored the hypothesis that gamma secretase binds with normal presenilin so that it can cleave APP within the membrane.