Abstract
Disease-associated amyloid deposits contain both fibrillar and nonfibrillar components. The majority of these amyloid components originate or coexist in the bloodstream. To understand the nature of the interaction between the nonfibrillar and fibrillar components, we have developed a centrifugation method to isolate fibril binding proteins from human serum. Amyloid fibrils composed of either Abeta peptide or apolipoprotein C-II (apoC-II) cosedimented with specific serum proteins. Gel electrophoresis, mass spectrometry peptide fingerprinting, and Western analysis identified the major binding species as proteins found in HDL particles, including apoA-I, apoA-II, apoE, clusterin, and serum amyloid A. Sedimentation analysis showed that purified human HDL and recombinant apoA-I lipid particles bound directly to Abeta and apoC-II amyloid fibrils. These studies reveal a novel function of HDL that may contribute to the well-established protective effect of this lipoprotein class in heart disease.
Highlights
Disease-associated amyloid deposits contain both fibrillar and nonfibrillar components
Mixtures of human serum and preformed a-synuclein, Ab peptide, or apolipoprotein C-II (apoC-II) amyloid fibrils were centrifuged through a 20% sucrose solution, and the pellet fraction was analyzed by SDS-PAGE
This study examines the direct interaction of serum proteins with preformed amyloid fibrils
Summary
Disease-associated amyloid deposits contain both fibrillar and nonfibrillar components. SAP protects serum amyloid A (SAA) and Ab amyloid fibrils from proteolysis by trypsin, chymotrypsin, and pronase [11], whereas apoE and SAP mediate the self-association and tangling of apoC-II amyloid fibrils [12] Another potential role for nonfibrillar components such as SAP is to affect the recognition of toxic oligomeric amyloid precursors [13] by the innate immune response. The Ab peptide, for example, is found in a variety of tissues but is deposited as fibrils only in synapses and the basement membranes of brain blood vessels [14] Such specificity suggests that there are factors, other than the nature of the fibril-forming proteins, that control amyloid deposition. Because the majority of nonfibrillar components in amyloid deposits are derived from, or at least coexist in, the Abbreviations: apoC-II, apolipoprotein C-II; SAA, serum amyloid A; SAP, serum amyloid P component
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