Heparan sulfate mediates amyloid-beta internalization and cytotoxicity.
Heparan sulfate (HS) has been found associated with amyloid deposits, including the toxic amyloid-beta (Abeta) peptide aggregates in cerebral vasculature and neuronal tissues in patients with Alzheimer's disease. However, the pathophysiological significance of the HS-Abeta interaction has remained unclear. In the present study, we applied cell models to gain insight into the roles of HS in relation to Abeta toxicity. Wild-type Chinese hamster ovary (CHO-WT) cells showed loss of viability following exposure to Abeta40, whereas the HS-deficient cell line, pgsD-677, was essentially resistant. Immunocytochemical analysis showed Abeta internalization by CHO-WT, but not pgsD-677 cells. Abeta40 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 Abeta40 and protected against Abeta toxicity. Taken together, these findings suggest that cell-surface HS mediates Abeta internalization and toxicity.
Sandwall
Elina
E
Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, SE-751 23, Uppsala, Sweden.
O'Callaghan
Paul
P
Zhang
Xiao
X
Lindahl
Ulf
U
Lannfelt
Lars
L
Li
Jin-Ping
JP
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005966:Glucuronidase / Q000096:biosynthesis / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D013329:Structure-Activity Relationship; D000099175:Heparanase
D016229:Amyloid beta-Peptides; D005966:Glucuronidase; D006493:Heparin; D006497:Heparan Sulfate; D000099175:Heparanase