High density lipoproteins bind A b and apolipoprotein CII amyloid fibrils 1

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 Ab peptide or apolipoprotein C-II (apoC-II) cosedimented with specific serum proteins. Gel electrophoresis, mass spectrometry peptide fingerprinting, andWestern analysis identified themajor binding species as proteins found in HDL particles, including apoA-I, apoA-II, apoE, clusterin, and serum amyloid A. Sedimentation analysis showed that purified humanHDL and recombinant apoA-I lipid particles bound directly to Ab 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. —Wilson, L. M. , C. L. L. Pham, A. J. Jenkins, J. D. Wade, A. F. Hill, M. A. Perugini, and G. J. Howlett. High density lipoproteins bind Ab and apolipoprotein C-II amyloid fibrils. J. Lipid Res. 2006. 47: 755–760. Supplementary key words amyloidosis . apolipoprotein A-I . atherosclerosis . human serum . lipid . nonfibrillar component . protein aggregation . protein folding Amyloid deposits are associated with a large number of debilitating disorders, including Alzheimer’s and Parkinson’s diseases, transmissible spongiform encephalopathies, type II diabetes, and systemic amyloidoses (1). More than 20 different polypeptides and proteins form amyloid fibrils in vivo; the majority of these are derived from the bloodstream and are deposited extracellularly (2). Amyloid fibrils are universally characterized by their interaction with the dyes thioflavin T and Congo Red and by their cross-b structure, as revealed by X-ray diffraction. Recent work has focused on the molecular structure of amyloid fibrils, with a particular focus on the organization of the cross-b sheets formed by the Ab peptide (3) and the X-ray crystallography of amyloid fibrils composed of small peptides (4, 5). Less attention has been focused on the nonfibrillar components of amyloid deposits, such as serum amyloid P component (SAP), apolipoprotein E (apoE), clusterin (apoJ), and glycoproteins such as laminin and agrin (6). Although several potential roles for these molecules in the deposition of amyloidplaques have beenproposed, conflictingdatahave confused their precise function. For example, studieswith the Ab peptide show that apoE and SAP promote Ab fibril formation (7, 8), whereas other work shows that apoE and SAP inhibit Ab fibril formation (9, 10). Nonfibrillar components may also affect the stability and interaction within amyloiddeposits. SAPprotects serumamyloidA (SAA) and Ab amyloid fibrils from proteolysis by trypsin, chymotrypsin, and pronase (11), whereas apoE and SAP also 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. Amyloid deposits are often localized to specific tissues, with peptides accumulating in restricted locations (1). 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 Manuscript received 30 September 2005 and in revised form 21 November 2005 and in re-revised form 21 December 2005. Published, JLR Papers in Press, January 23, 2006. DOI 10.1194/jlr.C500022-JLR200 Abbreviations: apoC-II, apolipoprotein C-II; SAA, serum amyloid A; SAP, serum amyloid P component. 1 To whom correspondence should be addressed. e-mail: ghowlett@unimelb.edu. au The online version of this article (available at http://www.jlr.org) contains an additional table. Copyright D 2006 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr. org Journal of Lipid Research Volume 47, 2006 755 by gest, on A uust 8, 2017 w w w . j.org D ow nladed fom 0.DC1. html http://www.jlr. org/content/suppl/2006/01/26/C500022-JLR20 Supplemental Material can be found at: