AMYLOID PRECURSOR PROTEIN PROCESSING IN STEROL REGULATORY ELEMENT-BINDING PROTEIN SITE-2 PROTEASE-DEFICIENT CHINESE-HAMSTER OVARY CELLS

Amyloid peptides of 39-43 amino acids (A beta) are the major constitue nts of amyloid plaques present in the brains of Alzheimer's (AD) patie nts. Proteolytic processing of the amyloid precursor protein (APP) by the yet unidentified beta- and gamma-secretases leads to the generatio n of the amyloidogenic A beta peptides. Recent data suggest that all o f the known mutations leading to early onset familial AD alter the pro cessing of APP such that increased amounts of the 42-amino acid form o f A beta are generated by a gamma-secretase activity. Identification o f the beta- and/or gamma-secretases is a major goal of current AD rese arch, as they are prime targets for therapeutic intervention in AD. It has been suggested that the sterol regulatory element-binding protein site 2 protease (S2P) may be identical to the long sought gamma-secre tase. We have directly tested this hypothesis using over-expression of the S2P cDNA in cells expressing APP and by characterizing APP proces sing in mutant Chinese hamster ovary cells that are deficient in S2P a ctivity and expression. The data demonstrate that S2P does not play an essential role in the generation or secretion of A beta peptides from cells, thus it is unlikely to be a gamma-secretase.