Abstract
Inflammation-related (AA) amyloidosis is a severe clinical disorder characterized by the systemic deposition of the acute-phase reactant serum amyloid A (SAA). SAA is normally associated with the high-density lipoprotein (HDL) fraction in plasma, but under yet unclear circumstances, the apolipoprotein is converted into amyloid fibrils. AA amyloid and heparan sulfate (HS) display an intimate relationship in situ, suggesting a role for HS in the pathogenic process. This study reports that HS dissociates SAA from HDLs isolated from inflamed mouse plasma. Application of surface plasmon resonance spectroscopy and molecular modeling suggests that HS simultaneously binds to two apolipoproteins of HDL, SAA and ApoA-I, and thereby induce SAA dissociation. The activity requires a minimum chain length of 12-14 sugar units, proposing an explanation to previous findings that short HS fragments preclude AA amyloidosis. The results address the initial events in the pathogenesis of AA amyloidosis.
Highlights
Serum amyloid A (SAA) is normally associated with the high-density lipoprotein (HDL)
The addition of heparin to HDL isolated from normal mouse plasma did not result in fibril formation
The central issue in the pathogenesis of AA amyloidosis is the conversion of circulating serum amyloid A (SAA) into amyloid fibrils
Summary
Serum amyloid A (SAA) is normally associated with the high-density lipoprotein (HDL). The procedure causes amyloid formation in affected organs within 24 h [7] Experiments with this model have revealed an intimate structural and temporal relationship between AA amyloidosis and heparan sulfate (HS) [8], a sulfated polysaccharide expressed on the cell surfaces and in the extracellular matrix, suggesting a role for HS in SAA amyloidogenesis. The. Heparan Sulfate Dissociates Serum Amyloid A from HDL overexpression of heparanase resulted in a drastic shortening of the HS chain length, demonstrating a decisive role for the polysaccharide chain length in SAA aggregation. The results reveal that HS/heparin-SAA interaction causes SAA to dissociate from the HDL-SAA complex at mild acidic conditions This process is critically dependent on the molecular size of the polysaccharide. The results offer an explanation for earlier observations and, most importantly, provide information for the potential management of AA amyloidosis by targeting HS-SAA interaction
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