Raft lipids as common components of human extracellular amyloid fibrils

Abstract

Amyloid fibrils are fibrillar polypeptide aggregates from several degenerative human conditions, including Alzheimer's and Creutzfeldt-Jakob diseases. Analysis of amyloid fibrils derived from various human diseases (AA, ATTR, A␤2M, AL , and AL amyloidosis) shows that these are associated with a common lipid component that has a conserved chemical composition and that is specifically rich in cholesterol and sphingolipids, the major components of cellular lipid rafts. This pattern is not notably affected by the purification procedure, and no tight lipid interactions can be detected when preformed fibrils are mixed with lipids. By contrast, the early and prefibrillar aggregates formed in an AA amyloidproducing cell system interact with the raft marker ganglioside-1, and amyloid formation is impaired by addition of cholesterolreducing agents. These data suggest the existence of common cellular mechanisms in the generation of different types of clinical amyloid deposits.protein folding ͉ prion ͉ lipid rafts

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

“…18). The initial adhesion of cells to amyloids could be spontaneous, consistent with their membrane binding property (86) and as observed here with adhesion of RBCs to kassinin amyloid fibrils. Subsequent to the initial immobilization of cells on amyloid surfaces, cell spreading and motility require integrin engagement and formation/turnover of focal adhesions (88,89).…”

“…Moreover, amyloids possess a highly repetitive cross-␤-sheet structure and a unique combination of charge and hydrophobic surfaces, which makes them sticky (22,84,85). It is perhaps these combinatorial features that enable amyloids to bind to membrane with high affinity (86). These properties of amyloids are utilized by lower organisms for their ECM formation (87).…”

Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits

“…S8E) is also consistent with literature values for biological membranes (21)(22)(23). Lipids represent, besides SAP and GAGs, an additional class of nonfibril components of disease-associated, extracellular amyloid deposits (16,24) and were previously shown to interact with many amyloidforming polypeptide chains (25), to promote fibril formation in vitro (25), and to mediate the amyloid-dependent enhanced infectivity of HIV-1 to cultured cells (26).…”

“…This acute-phase protein is secreted by the liver in response to chronic inflammation and released into the blood, where it associates with high-density lipoprotein (HDL) particles. The cell model reproduces crucial features of fibril formation from SAA1 protein in vivo, such as the involvement of macrophages (11); the fragmentation of SAA1 protein (15); and the association of fibrils with secondary components, such as glycosaminoglycans (GAGs) and lipids (13,16). Due to its ready accessibility, we use it here for further analysis with electron tomography.…”

Electron Microscopy in the Diagnosis of Amyloidosis

“…These do not form fibrils in vitro, but are implicated in amyloid deposition and stability. Non fibrillar components, commonly present in various types of amyloid deposits, include: proteins (serum amyloid P component SAP, apolipoprotein E), proteoglycans -PG-(condroitinsulfate PG, heparansulfate PG) and lipids (Pettersson & Konttinen, 2010;Merlini et al, 2003;Gellermann et al, 2005). These are mostly or partially lost during extraction procedures, and they are not present in in vitro experiments.…”