Non-fibrillar components of amyloid deposits mediate the self-association and tangling of amyloid fibrils.
Amyloid deposits are proteinaceous extra-cellular aggregates associated with a diverse range of disease states. These deposits are composed predominantly of amyloid fibrils, the unbranched, beta-sheet rich structures that result from the misfolding and subsequent aggregation of many proteins. In addition, amyloid deposits contain a number of non-fibrillar components that interact with amyloid fibrils and are incorporated into the deposits in their native folded state. The influence of a number of the non-fibrillar components in amyloid-related diseases is well established; however, the mechanisms underlying these effects are poorly understood. Here we describe the effect of two of the most important non-fibrillar components, serum amyloid P component and apolipoprotein E, upon the solution behavior of amyloid fibrils in an in vitro model system. Using analytical ultracentrifugation, electron microscopy, and rheological measurements, we demonstrate that these non-fibrillar components cause soluble fibrils to condense into localized fibrillar aggregates with a greatly enhanced local density of fibril entanglements. These results suggest a possible mechanism for the observed role of non-fibrillar components as mediators of amyloid deposition and deposit stability.
MacRaild
Christopher A
CA
Russell Grimwade School of Biochemistry and Molecular Biology, Department of Chemical and Biomolecular Engineering, University of Melbourne, Victoria 3010, Australia.
Stewart
Cameron R
CR
Mok
Yee-Foong
YF
Gunzburg
Menachem J
MJ
Perugini
Matthew A
MA
Lawrence
Lynne J
LJ
Tirtaatmadja
Viyada
V
Cooper-White
Justin J
JJ
Howlett
Geoffrey J
GJ
D000682:Amyloid / Q000737:chemistry / Q000502:physiology*; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure*; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D016874:Neurofibrillary Tangles / Q000648:ultrastructure; D012212:Rheology; D000683:Serum Amyloid P-Component / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure*; D012965:Sodium Chloride / Q000494:pharmacology; D014783:Viscosity
D000682:Amyloid; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D000683:Serum Amyloid P-Component; D012965:Sodium Chloride