|Figure 1. Amyloid plaque production. A beta-secretase, BACE, cleaves the precursor protein (APP) and gamma-secretase cleaves the membrane-bound C99 fragment to release A beta from the membrane.|
beta-secretases have been implicated in the formation of the 4 kDa amyloid beta-peptide (A beta) found within amyloid plaques of Alzheimer’s disease. A beta is formed by the cleavage of beta-amyloid precursor protein (beta-APP) at its NH2-terminus by a beta-secretase, leaving a membrane bound fragment, C99. C99 can then be further cleaved by a gamma-secretase to release Abeta from the membrane (see Figure 1).
Although many candidates have been described over the years for beta-secretase, until now there has been little convincing evidence. Vassar et al.1 recently reported a candidate for the beta-secretase involved in Abeta formation. The protein, called beta-site APP-cleaving enzyme (BACE), exhibits all the properties expected for beta-secretase. BACE had not previously been recognized as an aspartic protease, since its activity is not inhibited by pepstatin. BACE has an optimum activity at pH 4.5. Cell studies have indicated that beta-secretase activity occurs in endosomal/lysosomal compartments, golgi-derived vesicles, and the endoplasmic reticulum. BACE immunostaining can be found mainly in the golgi and endosomes, with little staining in the endoplasmic reticulum and lysosomes. This is consistent with studies indicating that beta-secretase activity is found within acidic subcellular compartments.
Most peripheral tissues have low expression levels of BACE mRNA. In brain tissue, however, there is a uniformly higher expression of BACE mRNA. BACE expression is higher in neurons than in glia implicating neurons as the main source of A beta deposited in amyloid plaques. Overexpression of BACE results in increased beta-secretase cleavage of APP at known beta-secretase positions.
BACE maps to the long arm of chromosome 11.2 A BACE homolog, BACE2, has been identified on chromosome 21 in the portion that contains the obligate Down Syndrome region. BACE and BACE2 have 52% amino acid (aa) sequence homology and are divergent only at the COOH-terminal 30 aa and the NH2-terminal 80 aa. BACE2, however, does not appear to be the major beta-secretase and cannot compensate for loss of BACE function. BACE may be an important new therapeutic target for treatment of Alzheimer’s disease.