beta-Site
amyloid precursor
protein-cleaving
enzyme 1 (BACE1) is a membrane-bound aspartic
protease that cleaves
amyloid precursor
protein to produce a neurotoxic
peptide, Abeta, and is implicated in triggering the pathogenesis of
Alzheimer disease. We previously reported that BACE1 cleaved rat
beta-galactoside alpha2,6-sialyltransferase (
ST6Gal I) that was overexpressed in COS cells and that the NH(2) terminus of
ST6Gal I secreted from the cells (E41 form) was Glu(41). Here we report that BACE1 gene knock-out mice have one third as much plasma
ST6Gal I as control mice, indicating that BACE1 is a major
protease which is responsible for cleaving
ST6Gal I in vivo. We also found that BACE1-transgenic mice have increased level of
ST6Gal I in plasma. Secretion of
ST6Gal I from the liver into the plasma is known to be up-regulated during the
acute-phase response. To investigate the role of BACE1 in
ST6Gal I secretion in vivo, we analyzed the levels of BACE1
mRNA in the liver, as well as the plasma levels of
ST6Gal I, in a hepatopathological model, i.e. Long-Evans Cinnamon (LEC) rats. This rat is a mutant that spontaneously accumulates
copper in the liver and incurs hepatic damage. LEC rats exhibited simultaneous increases in BACE1
mRNA in the liver and in the E41 form of the
ST6Gal I protein, the BACE1 product, in plasma as early
as 6 weeks of age, again suggesting that BACE1 cleaves
ST6Gal I in vivo and controls the secretion of the E41 form.