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J. Biol. Chem., Vol. 280, Issue 34, 30001-30008, August 26, 2005

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Protofibril Formation of Amyloid -Protein at Low pH via a Non-cooperative Elongation Mechanism^*

Rita Carrotta, Mauro Manno, Donatella Bulone, Vincenzo Martorana, and Pier Luigi San Biagio

From the Italian National Research Council, Institute of Biophysics at Palermo, via U. La Malfa 153, I-90146 Palermo, Italy

Deposition of the amyloid -protein (A) in senile or diffuse plaques is a distinctive feature of Alzheimer's disease. The role of A aggregates in the etiology of the disease is still controversial. The formation of linear aggregates, known as amyloid fibrils, has been proposed as the onset and the cause of pathological deposition. Yet, recent findings suggest that a more crucial role is played by prefibrillar oligomeric assemblies of A that are highly toxic in the extracellular environment. In the present work, the mechanism of protofibril formation is studied at pH 3.1, starting from a solution of oligomeric precursors. By combining static light scattering and photon correlation spectroscopy, the growth of the mass and the size of aggregates are determined at different temperatures. Analysis and scaling of kinetic data reveal that under the studied conditions protofibrils are formed via a single non-cooperative elongation mechanism, not prompted by nucleation. This process is well described as a linear colloidal aggregation due to diffusion and coalescence of growing aggregates. The rate of elongation follows an Arrhenius law with an activation enthalpy of 15 kcal mol^–1. Such a value points to a conformational change of peptides or oligomers being involved in binding to protofibrils or in general to a local reorganization of each aggregate. These results contribute to establishing a clearer relation at the molecular level between the fibrillation mechanism and fibrillar precursors. The observation of a non-cooperative aggregation pathway supports the hypothesis that amyloid formation may represent an escape route from a dangerous condition, induced by the presence of toxic oligomeric species.

Received for publication, January 3, 2005 , and in revised form, April 29, 2005.

^* This work was partially supported by the Italian Ministero della Salute through the projects "Animal Neuropathies: Molecular and Functional Analyisis of Prion Protein in Sicilian Bovine Species" and "Deposit of Amyloid -Protein in Cellular Membrane: Role of Metal Ions and Free Radicals." 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. Tel.: 39-091-680-9305; Fax: 39-091-680-9349; E-mail: mauro.manno{at}pa.ibf.cnr.it.

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