Identification of a novel aspartic protease (Asp 2) as beta-secretase

The Alzheimer's disease beta-amyloid peptide (Ap) is produced by excision f rom the type 1 integral membrane glycoprotein amyloid precursor protein (AP P) by the sequential actions of beta- and then gamma-secretases. Here we re port that Asp 2, a novel transmembrane aspartic protease, has the key activ ities expected of beta-secretase. Transient expression of Asp 2 in cells ex pressing APP causes an increase in the secretion of the N-terminal fragment of APP and an increase in the cell-associated C-terminal beta-secretase AP P fragment. Mutation of either of the putative catalytic aspartyl residues in Asp 2 abrogates the production of the fragments characteristic of cleava ge at the beta-secretase site. The enzyme is present in normal and Alzheime r's disease (AD) brain and is also found in cell lines known to produce A b eta. Asp 2 localizes to the Golgi/endoplasmic reticulum in transfected cell s and shows clear colocalization with APP in cells stably expressing the 75 1-amino-acid isoform of APP.