Non-fibrillar components of amyloid deposits mediate the self-association and tangling of amyloid fibrils |
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Authors: | MacRaild Christopher A Stewart Cameron R Mok Yee-Foong Gunzburg Menachem J Perugini Matthew A Lawrence Lynne J Tirtaatmadja Viyada Cooper-White Justin J Howlett Geoffrey J |
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Institution: | Russell Grimwade School of Biochemistry and Molecular Biology, Department of Chemical and Biomolecular Engineering, University of Melbourne, Victoria 3010, Australia. |
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Abstract: | 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. |
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