Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors - PubMed (original) (raw)

. 2000 Nov 3;275(44):34086-91.

doi: 10.1074/jbc.M005430200.

J D Bradley, C M Rominger, D H Rominger, F Yang, J E Meredith Jr, Q Wang, A H Roach, L A Thompson, S M Spitz, J N Higaki, S R Prakash, A P Combs, R A Copeland, S P Arneric, P R Hartig, D W Robertson, B Cordell, A M Stern, R E Olson, R Zaczek

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Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors

D Seiffert et al. J Biol Chem. 2000.

Free article

Abstract

Presenilins are integral membrane protein involved in the production of amyloid beta-protein. Mutations of the presenilin-1 and -2 gene are associated with familial Alzheimer's disease and are thought to alter gamma-secretase cleavage of the beta-amyloid precursor protein, leading to increased production of longer and more amyloidogenic forms of A beta, the 4-kDa beta-peptide. Here, we show that radiolabeled gamma-secretase inhibitors bind to mammalian cell membranes, and a benzophenone analog specifically photocross-links three major membrane polypeptides. A positive correlation is observed among these compounds for inhibition of cellular A beta formation, inhibition of membrane binding and cross-linking. Immunological techniques establish N- and C-terminal fragments of presenilin-1 as specifically cross-linked polypeptides. Furthermore, binding of gamma-secretase inhibitors to embryonic membranes derived from presenilin-1 knockout embryos is reduced in a gene dose-dependent manner. In addition, C-terminal fragments of presenilin-2 are specifically cross-linked. Taken together, these results indicate that potent and selective gamma-secretase inhibitors block A beta formation by binding to presenilin-1 and -2.

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