Accumulation of the amyloid-beta (Abeta) plaque in the cerebral cortex is a critical event in the pathogenesis of Alzheimer's disease. Abeta peptide is generated by proteolytic cleavage of the beta-amyloid protein precursor (APP) at beta- and gamma-sites by proteases. The long-soμght beta-secretase was recently identified by several groups independently and designated beta-site APP cleaving enzyme (BACE) and aspartyl protease 2 (Asp2). A BACE homolog was recently cloned and designated BACE2, Asp1, DRAP (for Down region aspartic protease), and memapsin 1. BACE2 also cleaves APP at beta-site and at a different site within Abeta. BACE2 locates on chromosome 21q22.3, the so-called 'Down critical region', sμggesting that BACE2 and Abeta may also contribute to the pathogenesis of Down syndrome.