EVIDENCE THAT THE 42-AMINO-ACID AND 40-AMINO-ACID FORMS OF AMYLOID-BETA PROTEIN ARE GENERATED FROM THE BETA-AMYLOID PRECURSOR PROTEIN BY DIFFERENT PROTEASE ACTIVITIES

Cerebral deposition of the amyloid beta protein (A beta) is an early a nd invariant feature of Alzheimer disease (AD), Whereas the 40-amino a cid form of A beta (A beta(40)) accounts for approximate to 90% of all A beta normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidog enic it-residue form (A beta(42)), accounting for only approximate to 10% of secreted A beta, is deposited in the earliest phase of AD and r emains the major constituent of most amyloid plaques throughout the di sease, Moreover, its levels have been shown to be increased in all kno wn forms of early-onset familial AD, Thus, inhibition of A beta(42) pr oduction is a prime therapeutic goal. The same protease, gamma-secreta se, is assumed to generate the C termini of both A beta(40) and A beta (42). Herein, we analyze the effect of the compound MDL 28170, previou sly suggested to inhibit gamma-secretase, on beta-amyloid precursor pr otein processing, By immunoprecipitating conditioned medium of differe nt cell lines with various A beta(40)- and A beta(42)-specific antibod ies, we demonstrate a much stronger inhibition of the gamma-secretase cleavage at residue 40 than of that at residue 42, These data suggest that different proteases generate the A beta(40) and A beta(42) C term ini, Further, they raise the possibility of identifying compounds that do not interfere with general beta-amyloid precursor protein metaboli sm, including A beta(40) production, but specifically block the genera tion of the pathogenic A beta(42) peptide.