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J. Biol. Chem., Vol. 279, Issue 20, 21038-21045, May 14, 2004

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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¶, and Geoffrey J. Howlett||

From the Russell Grimwade School of Biochemistry and Molecular Biology, and ^¶Particulate Fluids Processing Centre, Department of Chemical and Biomolecular Engineering, University of Melbourne, Victoria 3010, Australia and Commonwealth Scientific and Industrial Research Organization, Parkville, Victoria 3052, Australia

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, -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.

Received for publication, December 22, 2003 , and in revised form, February 18, 2004.

^* This work was supported by the Australian Research Council and the National Health and Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Russell Grimwade School of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia. Tel.: 613-8344-7632; Fax: 613-9347-7730; E-mail: ghowlett{at}unimelb.edu.au.

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