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  • Title: Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer's disease.
    Author: Snow AD, Kinsella MG, Parks E, Sekiguchi RT, Miller JD, Kimata K, Wight TN.
    Journal: Arch Biochem Biophys; 1995 Jun 20; 320(1):84-95. PubMed ID: 7793988.
    Abstract:
    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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