1. Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA

Correspondence to: Sukanto Sinha Correspondence and requests for materials should be addressed to S.S. (e-mail: Email: ssinha@elanpharma.com). The nucleotide sequence of p501 has been deposited in the GenBank under accession number AF201468.

Abstract

Proteolytic processing of the amyloid precursor protein (APP) generates amyloid (A) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by -secretase at the amino terminus of the A peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of -cleaved soluble APP¹, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by -secretase(s) leads to the formation of A. The pathogenic mutation K670M671 N670L671 at the -secretase cleavage site in APP², which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased -secretase cleavage of the mutant substrate³. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the -secretase cleavage site, and find it to be the predominant -cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for -secretase. Cloning and expression of the enzyme reveals that human brain -secretase is a new membrane-bound aspartic proteinase.