Non-fibrillar components of amyloid deposits mediate the self-association and tangling of amyloid fibrils

Christopher A. MacRaild, Cameron R. Stewart, Yee Foong Mok, Menachem J. Gunzburg, Matthew A. Perugini, Lynne J. Lawrence, Viyada Tirtaatmadja, Justin J. Cooper-White, Geoffrey J. Howlett

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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, β-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.

Original languageEnglish
Pages (from-to)21038-21045
Number of pages8
JournalJournal of Biological Chemistry
Issue number20
Publication statusPublished - 14 May 2004
Externally publishedYes

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