Human brain beta-secretase contains heparan sulfate glycoconjugates

A polyclonal antibody against the 68 kDa beta-secretase was established, which recognizes a single 68 kDa band in brain homogenate of Alzheimer's disease patients and normal aged. Western analysis revealed that the protease is an acidic glycoprotein with negative charge on its glycoconjugate(s). Sensitiveness to heparitinase and glycopeptidase A indicates that the protease contains asparagine-linked oligosaccharide with heparan sulfate moieties. Specific detection of the 68 kDa band in the analysis using anti-heparan sulfate antibody, and its time-course-dependent degradation, also confirm the above results. It seems that, like human blood coagulation factors IXa and XIa, the glycoconjugate(s) attached to the protease interfere with substrate specificity, stability and topological restriction of proteolysis in brain extracellular matrix, where diffuse plaque formation is taking place.