07 Dec 2001

Yue-Ming Li, Merck and Company, began his presentation by reviewing the known biology of γ-secretase, a membrane-bound protease that cleaves within the transmembrane region of APP to generate the C-termini of the two predominant forms of Aβ known as Aβ40 and Aβ42, which are major constituents of SPs in AD brains. Further, Dr. Li pointed out that presenilin 1 (PS1) and presenilin 2 (PS2) are polytopic membrane spanning proteins that harbor mutations which give rise to early onset familial AD, and he then reviewed recent biochemical studies which provide compelling evidence that presenilins are novel aspartyl proteases that mediate γ-secretase activity when engaged in the putative γ-secretase macromolecular complex. PS1 and PS2 activities can be discriminated from one another on the basis of their susceptibility to inhibition by a potent γ-secretase inhibitor. Thus, Dr. Li concluded that presenilin/γ-secretase is a potential target for AD therapy and plays an important role in regulated intramembrane proteolysis. However, as with the efforts described above to develop β-secretase inhibitor therapy for AD, there is little published preclinical data on γ-secretase inhibitors upon which to base solid predictions on the merits of this approach to the therapy of AD.—John Trojanowski