Carrotta Rita, Manno Mauro, Bulone Donatella, Martorana Vincenzo, San Biagio Pier Luigi
Italian National Research Council, Institute of Biophysics at Palermo, via U. La Malfa 153, I-90146 Palermo, Italy.
J Biol Chem. 2005 Aug 26;280(34):30001-8. doi: 10.1074/jbc.M500052200. Epub 2005 Jun 28.
Deposition of the amyloid beta-protein (Abeta) in senile or diffuse plaques is a distinctive feature of Alzheimer's disease. The role of Abeta 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 Abeta 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.
β-淀粉样蛋白（Aβ）在老年斑或弥漫性斑块中的沉积是阿尔茨海默病的一个显著特征。Aβ聚集体在该疾病病因学中的作用仍存在争议。线性聚集体（即淀粉样纤维）的形成被认为是病理沉积的起始和原因。然而，最近的研究结果表明，Aβ的原纤维前寡聚体组装体在细胞外环境中具有高度毒性，发挥着更为关键的作用。在本研究中，从寡聚体前体溶液开始，在pH 3.1条件下研究了原纤维的形成机制。通过结合静态光散射和光子相关光谱，在不同温度下测定聚集体的质量和尺寸的增长情况。动力学数据的分析和标度表明，在所研究的条件下，原纤维是通过单一的非协同延伸机制形成的，不是由成核引发的。由于生长聚集体的扩散和聚并，这个过程可以很好地描述为线性胶体聚集。延伸速率遵循阿伦尼乌斯定律，活化焓为15 kcal mol⁻¹。这样的值表明肽或寡聚体的构象变化参与了与原纤维的结合，或者一般来说参与了每个聚集体的局部重组。这些结果有助于在分子水平上更清楚地建立纤维化机制与纤维状前体之间的关系。非协同聚集途径的观察支持了这样的假设，即淀粉样蛋白的形成可能代表了由有毒寡聚体物种的存在所诱导的危险状态的一种逃逸途径。
