A is generated by endoproteolytic processing of the acid similarity and both have a C-terminal transmemlarge type I transmembrane protein, amyloid precursor brane domain. However, BACE and BACE2 are only protein (APP; Figure 1). Enzymes called-and-secre-40% similar to other aspartic proteases in the pepsin tase cleave APP to form the N and C termini, respecfamily, suggesting that BACE and BACE2 define a novel tively, of the A peptide.-secretase is the rate-limiting family (Figure 2). enzyme in the production of A and cleaves APP first The chromosomal localization of the BACE gene is to form the membrane-bound C99 fragment, which in 11q23. 3, a locus not associated with AD, while that of turn is the substrate of-secretase (Figure 1). Clearly, the BACE2 gene is chromosome 21 within the critical the-and-secretases are excellent therapeutic tar-Down’s syndrome region (Saunders et al., 1999). Theregets, and major efforts to identify these enzymes have fore, Down’s patients, who all develop AD by middle been pursued for over 12 years. Last fall, the long-sought age, have three copies each of the APP gene (also on

-secretase was identified as the novel transmembrane chromosome 21) and the BACE2 gene. This observation aspartic protease BACE (for beta-site APP cleaving ensuggested that BACE2 may be involved in the AD patholzyme), and several recent papers suggest that researchogy of Down’s syndrome (Saunders et al., 1999). Howers may be close to identifying the-secretase. In this ever, to date the evidence supporting this hypothesis review, we discuss these recent advances and their imis weak. First, BACE2 is expressed at very low levels in plications for-and-secretase research and therapeumost neurons of the brain and therefore has a pattern tic development. of expression inconsistent with that expected of-secre-