Aβ-Generating Enzymes Recent Advances in β- and γ-Secretase Research

is higher in neurons of the brain. (2) BACE is localized within acidic intracellular compartments. (3) Overex-pression of BACE in cells increases ␤-secretase cleav-age products; these products start only at known ␤-secre-tase cleavage sites. (4) Antisense inhibition of BACE in cells decreases ␤-secretase cleavage. (5) Purified forms of BACE cleave APP substrates in vitro with correct ␤-secretase specificity. (6) BACE has an acidic pH opti-Alzheimer's Disease (AD) is characterized by two hallmark mum and is not inhibited by the common aspartic prote-lesions in the brain: the extracellular amyloid plaques, pri-ase inhibitor pepstatin. Taken together, all the properties marily composed of the 40-42 amino acid A␤ peptide, and of BACE match one-to-one with those of ␤-secretase. the intracellular neurofibrillary tangles made of abnormally BACE2 phosphorylated tau, a microtubule-associated protein. Al-Soon after the discovery of BACE, a homologous gene, though the cause of AD is controversial, most evidence BACE2 (also called Asp1 or Memapsin1), was identified supports a central role for A␤ in the pathogenesis of the by searching genome databases (Saunders et al., 1999; disease (for review, see Selkoe, 1999). Bennett et al., 2000). BACE and BACE2 share 64% amino A␤ is generated by endoproteolytic processing of the acid similarity and both have a C-terminal transmem-large type I transmembrane protein, amyloid precursor brane domain. However, BACE and BACE2 are only protein (APP; Figure 1). Enzymes called ␤-and ␥-secre-‫%04ف‬ similar to other aspartic proteases in the pepsin tase cleave APP to form the N and C termini, respec-family, 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). There-gets, 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 en-suggested that BACE2 may be involved …