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1.
Glycobiology ; 20(5): 533-41, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20053627

RESUMO

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.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Heparitina Sulfato/metabolismo , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucuronidase/biossíntese , Glucuronidase/metabolismo , Heparina/farmacologia , Humanos , Relação Estrutura-Atividade
2.
J Biol Chem ; 284(6): 3814-22, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19068480

RESUMO

Spalax, a subterranean blind mole rat, is well adapted to live in an extreme hypoxic environment through up-regulated expression of growth factors and enzymes for ensuring sufficient oxygen supply. One of the overexpressed enzymes is heparanase, an endoglucuronidase that selectively cleaves heparan sulfate (HS) and is implicated in angiogenesis. To assess the implications of the heparanase in Spalax, we have characterized the structure of HS isolated from various organs of the animal. The oligosaccharides obtained after deaminative cleavage of HS samples from the tissues show an overall higher sulfation degree, distinct from that of murine tissues. Of particular significance was the appearance of a trisaccharide moiety in the tissues examined, apart of the even numbered oligosaccharide fractions typically found in HS from human and mouse tissues. The formation of this odd-numbered saccharide is a consequence of heparanase action, in agreement with the notion of high expression of the enzyme in this species. Analysis of HS extracted from human embryonic kidney cells (HEK293) after exposure to hypoxic condition revealed a structural change in the distribution of oligosaccharides similar to HS derived from Spalax organs. The alterations are likely due to up-regulated activity of heparanase, as real-time RT-PCR showed a 2-fold increase in heparanase mRNA expression in the hypoxia treated cells. HEK293 cells stably overexpressing Spalax heparanase produced HS sharing similarity with that from the Spalax organs, and exhibited enhanced MAPK activity in comparison with HEK293 cells, indicating a regulation role of the heparanase in the activity of growth factors.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Glucuronidase/biossíntese , Heparitina Sulfato/metabolismo , Hipóxia/enzimologia , Neovascularização Fisiológica/fisiologia , Spalax/metabolismo , Animais , Sequência de Carboidratos/fisiologia , Hipóxia Celular/fisiologia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucuronidase/genética , Heparitina Sulfato/química , Heparitina Sulfato/genética , Humanos , Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Spalax/genética , Especificidade da Espécie
3.
Brain Pathol ; 18(4): 548-61, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18422760

RESUMO

Amyloid beta-peptide (Abeta) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in Abeta deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with Abeta plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the Abeta40 dense cores of neuritic plaques, but was largely absent from diffuse Abeta42 plaques, suggesting that Abeta42 deposition may occur independently of HS. A codeposition pattern of HS with Abeta deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with Abeta deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following Abeta stimulation. These results suggest that HS codeposits with Abeta40 in neuritic plaques and is mainly derived from glial cells.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Heparitina Sulfato/metabolismo , Neuroglia/metabolismo , Placa Amiloide/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Feminino , Glipicanas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neuroglia/patologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/patologia , Sindecana-3/metabolismo , Regulação para Cima/fisiologia
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