A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase

Down syndrome individuals develop abnormalities of most organs, including a ll the pathological and neurochemical features of Alzheimer's disease, by t he early age of 30 yr. Here, we report the isolation and characterization o f BACE2, a gene mapping on human chromosome 21q22.3, which is highly simila r to a transmembrane aspartyl protease, BACE (for beta-site APP-cleaving en zyme), which is able to catalyze the beta-secretase cleavage of Alzheimer's amyloid precursor protein (APP). BACE2 is expressed in a wide variety of o rgans and tissues, with several transcripts due to alternative splicing and the use of two polyadenylation signals. The BACE2 gene product is a 518 am ino acid protein with the signature of an aspartic protease, a 20-residue s ignal peptide, and two putative N-glycosylation sites. In addition, and sim ilarly to BACE, BACE2 differs from the other members of the human aspartic protease family in the number and distribution of putative disulfide bonds and in the presence of an extended C-terminal region which contains a predi cted transmembrane segment. BACE2 could be involved in the Alzheimer-like n europathology of Down syndrome, as well as in Alzheimer's disease linked to chromosome 21 but not showing mutations in APP. Copyright (C) 2000 S. Karg er AG, Basel.