Search

Alzheimer's beta-secretase (BACE1) cleaves amyloid precursor protein to produce amyloid beta-peptide, which is a crucial initiation process of the pathogenesis of Alzheimer's disease. We previously found that BACE1 also cleaves a membrane-bound sialyltransferase (ST6Gal I). Here we report that, when the protein A-ST6Gal I fusion protein, or ST6Gal I-derived peptide, was used as an in vitro substrate for BACE1, it cleaved the substrates between Leu(37) and Gln(38). However, a soluble form of ST6Gal I secreted from COS cells started from Glu(41), which was three amino acids shorter than the in vitro product. The results suggested that the BACE1 product was truncated by an aminopeptidase(s) before secretion. The aminopeptidase activity was successfully detected in detergent extracts of Golgi-membrane fraction. Taken together, we concluded that BACE1 initially cleaved ST6Gal I between Leu(37) and Gln(38), and the NH(2)-terminal three amino acids of the yielded product was further trimmed by the aminopeptidase.

Alzheimer's beta-secretase (BACE1) is a membrane-bound protease that cleaves the amyloid precursor protein (APP) in the trans-Golgi network, an initial step in the pathogenesis of Alzheimer's disease. Although BACE1 is distributed among various tissues including brain, its physiological substrate other than APP have not been identified. We have recently found that when BACE1 was overexpressed in COS cells together with alpha2,6-sialyltransferase (ST6Gal I), the secretion of ST6Gal I markedly increased, suggesting that BACE1 cleaves ST6Gal I as a physiological substrate. Thus BACE1 is the first identified protease that is responsible for the cleavage and secretion of glycosyltransferases.