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 ectodmain, Asp93 and Asp289, that are required for activity.

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

4. 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

5. 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).

6. 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).

7. 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).

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

9. 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.

10. 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.

11. 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).