Proteoglycan-mediated inhibition of A beta proteolysis. A potential cause of senile plaque accumulation.
Senile plaques of Alzheimer's disease brain contain, in addition to beta amyloid peptide (A beta), multiple proteoglycans. Systemic amyloidotic deposits also routinely contain proteoglycan, suggesting that these glycoconjugates are generally involved in amyloid plaque formation and/or persistence. We demonstrate that heparan sulfate proteoglycan (HSPG) and chondroitin sulfate proteoglycan (CSPG) inhibit the proteolytic degradation of fibrillar, but not non-fibrillar, A beta at physiological pH. In accordance with the proteolysis studies, high affinity binding of proteoglycans to fibrillar A beta(1-40) and A beta(1-42) is observed from pH 4 to 9, whereas appreciable binding of HSPG or CSPG to non-fibrillar peptide is only seen at pH < 6. This differing pH dependence of binding suggests that a lysine residue is involved in proteoglycan association with fibrillar A beta, whereas a protonated histidine appears to be needed for binding of the glycoconjugates to non-fibrillar peptide. Scatchard analysis of fibrillar A beta association with proteoglycans indicates a single affinity interaction, and the binding of both HSPG and CSPG to fibrillar A beta is completely inhibited by free glycosaminoglycan chains. This implies that these sulfated carbohydrate moieties are primarily responsible for proteoglycan.A beta interaction. The ability of proteoglycans to bind fibrillar A beta and inhibit its proteolytic degradation suggests a possible mechanism of senile plaque accumulation and persistence in Alzheimer's disease.
Gupta-Bansal
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Discovery Research Group, Gliatech Inc., Cleveland, Ohio 44122, USA.
Frederickson
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Brunden
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D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003871:Dermatan Sulfate / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010206:Papain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002401:Cathepsin B; D011508:Chondroitin Sulfate Proteoglycans; D003546:Cysteine Endopeptidases; D003871:Dermatan Sulfate; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D010206:Papain; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011509:Proteoglycans; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C032649:dermatan sulfate proteoglycan