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Proteolytic processing of the amyloid precursor protein (APP) generates amyloid [beta] (A[beta]) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by [beta]-secretase at the amino terminus of the A[beta] peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of [beta]-cleaved soluble APP 1, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by [gamma]-secretase(s) leads to the formation of A[beta]. The pathogenic mutation K670M671 -> N670L671 at the [beta]-secretase cleavage site in APP 2, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased [beta]-secretase cleavage of the mutant substrate 3. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the [beta]-secretase cleavage site, and find it to be the predominant [beta]-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 [beta]-secretase. Cloning and expression of the enzyme reveals that human brain [beta]-secretase is a new membrane-bound aspartic proteinase.

©: 1999 Macmillian Magazines Ltd