Heparan sulfate mediates amyloid-beta internalization and cytotoxicity

Heparan sulfate (HS) has been found associated with amyloid deposits, including the toxic amyloid-beta (A beta) peptide aggregates in cerebral vasculature and neuronal tissues in patients with Alzheimer's disease. However, the pathophysiological significance of the HS-A beta interaction has remained unclear. In the present study, we applied cell models to gain insight into the roles of HS in relation to A beta toxicity. Wild-type Chinese hamster ovary (CHO-WT) cells showed loss of viability following exposure to A beta 40, whereas the HS-deficient cell line, pgsD-677, was essentially resistant. Immunocytochemical analysis showed A beta internalization by CHO-WT, but not pgsD-677 cells. A beta 40 toxicity was also attenuated in human embryonic kidney cells overexpressing heparanase. Finally, addition of heparin to human umbilical vein endothelial cells prevented internalization of added A beta 40 and protected against A beta toxicity. Taken together, these findings suggest that cell-surface HS mediates A beta internalization and toxicity.