Glycosaminoglycans inhibit neurodegenerative effects of serum amyloid P component in vitro.
Serum amyloid P component, a member of pentraxin serum protein family, has been suggested to contribute to the progression of neurodegeneration including Alzheimer's disease by binding to beta-amyloid fibrils leading to an increased stability of the deposits against proteolytic degradation and by inducing neuronal apoptosis. Here, we show that glycosaminoglycans inhibit both the serum amyloid P component-beta-amyloid interaction and the neurotoxic effect of serum amyloid P component. These effects correlate with the structure of glycosaminoglycans and show different structure-activity relationship in the case of the two different effects. While the efficacy of the inhibition on the serum amyloid P component-induced cell death increases with the uronic acid content, the inhibitory activity on the serum amyloid P component-beta-amyloid interaction decreases with the increasing uronic acid content of the glycosaminoglycans. The inhibitory effect of glycosaminoglycans on the interaction between the first component of the complement cascade (C1q) and beta-amyloid shows a similar structure-activity relationship as on the serum amyloid P component-beta-amyloid interaction. This suggests that glycosaminoglycans interfere with the binding site on beta-amyloid for serum amyloid P component and C1q. The functional consequence of this binding has been demonstrated by heparin which promotes the proteolysis of beta-amyloid in vitro in the presence of serum amyloid P component. Our results suggest that glycosaminoglycans might have therapeutical potential on the neurodegeneration reducing its progress.
Urbányi
Zoltán
Z
Laboratory of Molecular Neurobiological Research, Gedeon Richter Ltd., PO Box 27, H-1475 Budapest 10, Hungary. z.urbanyi@richter.hu
Forrai
Erika
E
Sárvári
Miklós
M
Likó
István
I
Illés
János
J
Pázmány
Tamás
T
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D014574:Uronic Acids / Q000737:chemistry
D016229:Amyloid beta-Peptides; D006025:Glycosaminoglycans; D018696:Neuroprotective Agents; D000683:Serum Amyloid P-Component; D014574:Uronic Acids; D015922:Complement C1q