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      Affinity Binding of Glycosaminoglycans with β 2-Microglobulin

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          Background: A constant finding in β<sub>2</sub>-microglobulin (β2m) amyloidosis is an increase in tissue heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) at sites of amyloid deposits. However, the binding characteristics of PGs with β2m have not been elucidated yet. Methods: Using affinity retardation chromatography, β2m- and glycosaminoglycan (GAG)-anchored columns, an affinity between β2m and GAGs was analyzed. Five peptides which spanned the entire β2m amino acid sequence were prepared, and an affinity between these peptides and heparin (HP) was examined. Furthermore, the specific binding of biotinylated β2m peptide for AA amyloid deposits via GAGs was examined on tissue sections. Results: Using β2m-anchored column, HP showed the smallest dissociation constant (K<sub>d</sub>), i.e. the strongest affinity, among the GAGs examined. At 0.4 M NaCl, the K<sub>d</sub>s of β2m relative to BSA-anchored columns for HP, HS, CS-A, CS-B, and CS-C were 94, 620, 130, 660 and 190 µ M, respectively. Using GAG-anchored columns, at 0.15 M NaCl, pH 7.4, β2m also showed an affinity for HP, with the K<sub>d</sub> relative to a reference column being 370 µ M. Under the latter conditions, no β2m affinity for CSA was demonstrated. Among the five peptides, peptide-1, which is composed of residues 1–24, showed the highest affinity for HP, the K<sub>d</sub> being 190 µ M. Peptides analogous to peptide-1, in which each basic amino acid was individually replaced by alanine, showed a remarkable decrease in affinity for HP. The specific binding of biotinylated β2m peptide for AA amyloid deposits via HS and CS was confirmed in situ by pretreatment with heparitinase and chondroitinase ABC. Conclusion: The present data indicate that HP/HS is effective in the binding of the β2m monomer, and the anatomic localization of β2m amyloid precursor protein.

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          Most cited references 8

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          Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease.

          Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.
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            Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer's disease.

            Previous studies have demonstrated the immunolocalization of perlecan, a specific heparan sulfate proteoglycan, to the beta-amyloid protein (A beta)-containing amyloid deposits within the walls of blood vessels (i.e., congophilic angiopathy) in Alzheimer's disease (AD) brain. In the present investigation, the differential binding of previously characterized endothelial cell (EC)- and smooth muscle cell (SMC)-derived PGs to A beta was examined to determine whether the accumulation of A beta in cerebrovascular amyloid deposits may be due to its interactions with perlecan. Pretreatment of AA amyloidotic splenic and liver tissue sections with synthetic A beta (1-28) produced strong immunoreactivity with A beta antibodies at tissue sites enriched in perlecan which was partially removed by pretreatment with heparitinase, but not by chondroitin ABC lyase. [35S]-Sulfate labeled proteoglycans (PGs) derived from cultured ECs and SMCs bound to affinity columns containing A beta (1-28) or (1-40), with virtually no binding to A beta (40-1) (reverse peptide), beta-amyloid precursor protein (410-429), or bovine serum albumin. Characterization of EC and SMC PGs bound to A beta (1-28) revealed strong binding by perlecan, weak binding by decorin and biglycan, two dermatan sulfate proteoglycans, and lack of binding by versican/PG-M, a large chondroitin sulfate proteoglycan. Binding of 125I-labeled perlecan to A beta (1-28) was strongly inhibited by isolated perlecan and to a lesser extent by heparin, but not by chondroitin-6-sulfate or unsulfated dextran sulfate. Heparitinase treatment decreased, but did not eliminate the binding of 125I-labeled perlecan to A beta (1-28). Scatchard analysis of the interaction of A beta (1-28)- and EC-derived perlecan in solid-phase assays indicated high-affinity (Kd = 8.3 x 10(-11) M) and lower-affinity (Kd = 4.2 x 10(-8) M) binding sites, with approximately 1 mol of perlecan binding 1.8 mol of A beta. A significant decrease in binding of EC-derived perlecan to A beta (1-28) was observed when a sequence within the putative heparin-binding motif of A beta (His13His14Gln15Lys16) was replaced by the uncharged peptide sequence, Gly13Gly14Gln15Gly16, indicating a perlecan binding site on A beta near the postulated alpha-secretase site (at Lys-16). Overall, the results indicate that specific vascular cell-derived PGs differentially interact with A beta, and that the interactions of highest affinity occur between A beta and binding sites on both the core protein and glycosaminoglycan chains of perlecan.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Autoantibodies in pathology and cell biology.

               Eng M. Tan (1991)

                Author and article information

                S. Karger AG
                February 2002
                30 January 2002
                : 90
                : 2
                : 158-168
                aDepartment of Pathology, Faculty of Medicine, and bDepartment of Biochemistry, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo, Japan, and cDepartment of Pathology, Queen’s University, Kingston,Canada
                49037 Nephron 2002;90:158–168
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 3, References: 39, Pages: 11
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/49037
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