BACE Maps to Chromosome 11 and a BACE Homolog, BACE2 , Reside in the Obligate Down Syndrome Region of Chromosome 21

Abstract

This implies that in addition to the contribution of a third copy of the APP gene (3), a third copy of BACE2 may also significantly contribute to enhanced amyloid-deposition inevitably observed in the brains of middle-aged DS patients. Based on these data, DS patients would be expected to not only express more substrate for amyloid-production (APP) but also more of a protease (BACE2) that would be predicted to cleave at the-secretase site of APP, thereby exacerbating the release of amyloid-. The identification of BACE and BACE2 as strong candidates for-secretase provides novel molecular targets for mechanis-tic (protein-based) high-throughput drug screening for specific protease inhibitors. Identification of such inhibitors could afford a potentially powerful new generation of AD and DS therapeutics. Furthermore, the precise chromosomal mapping of BACE and BACE2 to the long arms of chromosomes 11 and 21, respectively, should greatly facilitate attempts to test these genes for genetic linkage to AD.