Beta secretase (BACE)

1.  In 1999, beta-secretase was identified as a protein with homology to the pepsin family of aspartyl proteases (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999; Lin et al., 2000).

2. Beta-Secretase contains a single transmembrane domain near the COOH terminus, a signal sequence and propeptide region at the NH2 terminus, and two aspartates in its ectodomain, Asp93 and Asp289, that are required for activity.

3. B-secretase cleaves at the N-terminal site of Abeta (cartoon)

4. The responsible protease to activate beta secretase seems to be a furin-like protease (Bennett et al., 2000).

5. Beta- Secretase RNA is highly expressed in the brain and is also found in a variety of human tissues (Vassar et al., 1999; Yan et al., 1999; Lin et al., 2000), consistent with the finding that Abeta is normally produced by many cell types

6. The intracellular localization of beta-secretase protein is expressed primarily in the Golgi and in endosomes, whereas only a small amount of it can be detected in endoplasmic reticulum, lysosomes, and the plasma membrane (Vassar et al., 1999; Yan et al., 1999; Lin et al., 2000).

7. BACE is phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1, and the phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and N-glycosylation and drives the localization of BACE to Golgi compartments and endosome (Walter et al., 2001).

8. The gene for beta-secretase is located on chromosome 11, but no AD-causing mutation in this gene has been identified so far (Saunders et al., 1999).

9. A beta-secretase homolog, BACE-2, maps to chromosome 21, raising the possibility that BACE-2 contributes to Down syndrome.

10. There is very little of this protease in the brain, suggesting that it may play little if any role in the formation of cerebral plaques seen in AD.

11. BACE-2 is strongly expressed in heart, kidney, and placenta, suggesting that it may be important in highly vascularized systemic tissues (Farzan et al., 2000). It will be critical to develop drugs that selectively block BACE but not BACE-2.

12. BACE knockout mice seemed to abolish Abeta production totally and to develop normally, healthy, and fertile (Luo et al., 2001; Roberds et al., 2001), showing that the therapeutic of BACE for treatment of AD may be free of mechanism-based toxicity (Suh and Checler, 2002).

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    BETA-SECRETASE - PROGRESS AND QUESTIONS
    M. Citron
    Neuroscience M/S 29-2B, Amgen, USA
    Finding inhibitors of Ab42 generation is a major goal of Alzheimer’s disease
    drug development. Two target protease activities, b-and g-secretase, were
    operationally defined more than 10 years ago, but progress in this area has
    been slow, because the actual enzymes were not identified. Using an
    expression cloning strategy we have previously identified a novel membrane
    bound aspartic protease, BACE1, as b-secretase. This finding has been
    confirmed and BACE1 and its homolog BACE2 have been characterized in
    detail by many groups. Major progress has been made in two areas: First, the
    x-ray crystal structure, which is critical for rational inhibitor design, has been
    solved and shown to be similar to that of other pepsin family members.
    Second, knockout studies show that BACE1 is critical for Ab generation, but
    the knockout mice show an otherwise normal phenotype, raising the
    possibility that therapeutic BACE1 inhibition could be accomplished without
    major mechanism based toxicity. However, target-mediated toxicity of bsecretase
    inhibition cannot be ruled out based on the currently available data
    alone. While various peptidic b-secretase inhibitors have been published, the
    key challenge now is the generation of more drug-like compounds that could
    be developed for therapeutic purposes. Progress in several current areas of
    investigation, including identification of BACE1 substrates and the potential
    role of BACE1 overexpression in AD will be discussed.