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N-Unsubstituted Glucosamine Residues in Heparan Sulfate and Their Potential Relation to Alzheimer's Disease
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) is a linear polysaccharide, located on the surface and in the extracellular matrix of most cells, that regulates functions of numerous proteins. HS-protein interaction is mainly mediated by sulfate groups found in N-sulfated (NS) regions of the HS, but may also involve rare HS substituents such as N-unsubstituted glucosamine (GlcNH2) residues. The location of GlcNH2 in an HS-epitope recognized by the monoclonal antibody 10E4, that specifically stains the prion lesions in scrapie-infected murine brain, suggests an involvement of GlcNH2 in prion disease and other amyloid-related disorders. HS in general is strongly associated with amyloidosis, including Alzheimer’s disease (AD). Therefore, the aims of this thesis were to structurally characterize GlcNH2-containing HS sequences found in native tissues, to further study HS epitopes recognized by 10E4, and to investigate the possible role(s) of GlcNH2 and other HS structures in binding to amyloid β peptide (Aβ) (core material in AD plaque lesions, also stained by 10E4).

The GlcNH2 content (0.7-4% of total disaccharide units) varied between HS from different tissues. Most GlcNH2 units were found in poorly modified N-acetylated (NA-) or NA/NS-domains, located toward the polysaccharide-protein linkage region.

Binding of human cerebral cortex HS to Aβ(1–40) monomers requires N-, 2- and 6-O-sulfation of HS, while binding to Aβ fibrils requires N- and 2-O-sulfation only. GlcNH2 units do not appreciably contribute to interaction with Aβ. Aβ fibril-binding HS domains also bind to fibroblast growth factor 2 (FGF-2), indicating that Aβ (neurotoxic) and FGF-2 (neuroprotective) may compete for common binding sites in HS. However, Aβ had no effect on FGF-2-induced MAPK signaling in NIH 3T3 fibroblasts.

Continued studies on 10E4-antigenic HS epitope(s) showed that binding of 10E4 to the previously identified antigenic tetrasaccharide, ∆UA-GlcNH2-GlcA-GlcNAc, requires the nonreducing hexuronic acid (∆UA) to be 4,5 unsaturated (induced by lyase cleavage), and thus is artificial. Further studies are needed to clarify the potential involvement of GlcNH2 in 10E4-recognition of the native HS epitope(s).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 72
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1313
Keywords [en]
Biochemistry, heparan sulfate, N-unsubstituted glucosamine, Alzheimer's disease, amyloid beta peptide, amyloidosis, 10E4 antibody, fibroblast growth factor 2
Keywords [sv]
Biokemi
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-3866ISBN: 91-554-5825-4 (print)OAI: oai:DiVA.org:uu-3866DiVA, id: diva2:163801
Public defence
2004-01-30, C10:301, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-12-18 Created: 2003-12-18Bibliographically approved
List of papers
1. Common binding sites for beta-amyloid fibrils and fibroblast growth factor-2 in heparan sulfate from cerebral cortex
Open this publication in new window or tab >>Common binding sites for beta-amyloid fibrils and fibroblast growth factor-2 in heparan sulfate from cerebral cortex
1999 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 274, no 43, p. 30631-30635Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91163 (URN)
Available from: 2003-12-18 Created: 2003-12-18Bibliographically approved
2. Location of N-unsubstituted glucosamine residues in heparan sulfate
Open this publication in new window or tab >>Location of N-unsubstituted glucosamine residues in heparan sulfate
2002 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 277, no 51, p. 49247-49255Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91164 (URN)
Available from: 2003-12-18 Created: 2003-12-18Bibliographically approved
3. N-Unsubstituted glucosamine residues in heparan sulfate from human cerebral cortex: Relation to Alzheimer's disease?
Open this publication in new window or tab >>N-Unsubstituted glucosamine residues in heparan sulfate from human cerebral cortex: Relation to Alzheimer's disease?
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91165 (URN)
Available from: 2003-12-18 Created: 2003-12-18 Last updated: 2010-01-13Bibliographically approved
4. A tetrasaccharide determinant for heparan sulfate antibody 10E4 engineered from the polysaccharide of Escherichia coli serotype K5
Open this publication in new window or tab >>A tetrasaccharide determinant for heparan sulfate antibody 10E4 engineered from the polysaccharide of Escherichia coli serotype K5
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91166 (URN)
Available from: 2003-12-18 Created: 2003-12-18 Last updated: 2010-01-13Bibliographically approved

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