Accumulation of the amyloid-b (Ab) plaque in the cerebral cortex is a critical event in the pathogenesis of Alzheimer’s disease. Ab peptide is generated by proteolytic cleavage of the b-amyloid protein precursor (APP) at b-and g-sites by proteases. The long-sought b-secretase was recently identified by several groups independently and designated beta-site APP cleaving enzyme (BACE) and aspartyl protease 2 (Asp2) (1–4). A BACE homolog was recently cloned and designated BACE2, Asp1, DRAP (for Down region aspartic protease), and memapsin 1 (4–9). BACE2 also cleaves APP at b-site and at a different site within Ab (8). BACE2 locates on chromosome 21q22.3, the so-called ‘Down critical region’, suggesting that BACE2 and Ab may also contribute to the pathogenesis of Down syndrome (6,7)