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Articles by U Lindahl
Total Records ( 2 ) for U Lindahl
  E Sandwall , P O'Callaghan , X Zhang , U Lindahl , L Lannfelt and J. P. Li

Heparan sulfate (HS) has been found associated with amyloid deposits, including the toxic amyloid-beta (Aβ) peptide aggregates in cerebral vasculature and neuronal tissues in patients with Alzheimer's disease. However, the pathophysiological significance of the HS-Aβ interaction has remained unclear. In the present study, we applied cell models to gain insight into the roles of HS in relation to Aβ toxicity. Wild-type Chinese hamster ovary (CHO-WT) cells showed loss of viability following exposure to Aβ40, whereas the HS-deficient cell line, pgsD-677, was essentially resistant. Immunocytochemical analysis showed Aβ internalization by CHO-WT, but not pgsD-677 cells. Aβ40 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 Aβ40 and protected against Aβ toxicity. Taken together, these findings suggest that cell-surface HS mediates Aβ internalization and toxicity.

  J Jia , M Maccarana , X Zhang , M Bespalov , U Lindahl and J. P. Li

HSEPI (glucuronyl C5-epimerase) catalyzes the conversion of d-glucuronic acid to l-iduronic acid in heparan sulfate (HS) biosynthesis. Disruption of the Hsepi gene in mice yielded a lethal phenotype with selective organ defects but had remarkably little effect on other organ systems. We have approached the underlying mechanisms by examining the course and effects of FGF2 signaling in a mouse embryonic fibroblast (MEF) cell line derived from the Hsepi/ mouse. The HS produced by these cells is devoid of l-iduronic acid residues but shows up-regulated N- and 6-O-sulfation compared with wild type (WT) MEF HS. In medium fortified with 10% fetal calf serum, the Hsepi/ MEFs proliferated and migrated similarly to WT cells. Under starvation conditions, both cell types showed attenuated proliferation and migration that could be restored by the addition of FGF2 to WT cells, whereas Hsepi/ cells were resistant. Moreover, ERK phosphorylation following FGF2 stimulation was delayed in Hsepi/ compared with WT cells. Assessment of HS-growth factor interaction by nitrocellulose filter trapping revealed a strikingly aberrant binding property of FGF2 and glia-derived neurotropic factor to Hsepi/ but not to WT HS. glia-derived neurotropic factor has a key role in kidney development, defective in Hsepi/ mice. By contrast, Hsepi/ and WT HS interacted similarly and in conventional mode with FGF10. These findings correlate defective function of growth factors with their mode of HS interaction and may help explain the partly modest organ phenotypes observed after genetic ablation of selected enzymes in HS biosynthesis.

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