AMYLOID β BINDS TO ALBUMIN-ASSOCIATED LRP-LIKE PLASMA O-GLYCOPROTEINS; ALBUMIN PREVENTS INHIBITION OF BINDING BY LDL

Background: Albumin was reported to engage nearly 95% of plasma Amyloid beta (A beta) and to reverse A beta fibril formation in brain. Objective: Since O-glycosylated LRP family of receptors capture A beta in brain we compared AP binding to electrophoretically purified albumin and to O-glycoproteins AOP1 and AOP2 that adhere noncovalently to plasma albumin. Methods: Strength of A beta -protein interaction was measured as fluorescence increase in Fluorescent- labeled A beta (F-A beta ) resulting from conformational changes. Alternatively, differential segregation of free and protein-bound A beta in Density Gradient Ultracentrifugation (DGUC) was also examined. Results: Fluorescence enhancement in F-A beta was significantly greater by AOP1 and AOP2 than by known A beta reactants alpha-synuclein and -cyclodextrin, but nil by albumin. In DGUC A beta migrated with the O-glycoproteins but not with albumin. Free O-glycoproteins unlike their albumin-bound forms were blocked by LDL from capturing F-A beta. Associated albumin did not affect A beta binding of O-glycoproteins. De-O-glycosylation of AOP1/AOP2 enhanced their A beta binding showing that peptide sequences at O-glycosylated regions were recognized by A beta. Unlike albumin, AOP1 and AOP2 were immunologically cross-reactive with LRP. Albumin sample used earlier to report albumin-A beta interaction contained two O-glycoproteins cross-reactive with human LRP and equal in size to human AOP1 or AOP2. Conclusion: Unlike albumin, albumin-bound O-glycoproteins, immunologically cross-reactive with LRP, bind plasma A beta. These O-glycoproteins are potential anti-amyloidogenic therapeutics if they inhibit A beta aggregation as other A beta reactants do. Circulating immune complexes of albumin-bound O-glycoproteins with O-glycoprotein-specific natural antibodies can bind further to LRP-like membrane proteins and are possible O-glycoprotein transporters to tissues.