Tjernberg L O, Pramanik A, Björling S, Thyberg P, Thyberg J, Nordstedt C, Berndt K D, Terenius L, Rigler R
Laboratory of Biochemistry and Molecular Pharmacology, Section of Drug Dependence Research, Department of Clinical Neuroscience, the Karolinska Hospital, Stockholm, Sweden.
Chem Biol. 1999 Jan;6(1):53-62. doi: 10.1016/S1074-5521(99)80020-9.
The accumulation of fibrillar deposits of amyloid beta-peptide (Abeta) in brain parenchyma and cerebromeningeal blood vessels is a key step in the pathogenesis of Alzheimer's disease. In this report, polymerization of Abeta was studied using fluorescence correlation spectroscopy (FCS), a technique capable of detecting small molecules and large aggregates simultaneously in solution.
The polymerization of Abeta dissolved in Tris-buffered saline, pH 7.4, occurred above a critical concentration of 50 microM and proceeded from monomers/dimers into two discrete populations of large aggregates, without any detectable amount of oligomers. The aggregation showed very high cooperativity and reached a maximum after 40 min, followed by an increase in the amount of monomers/dimers and a decrease in the size of the large aggregates. Electron micrographs of samples prepared at the time for maximum aggregation showed a mixture of an amorphous network and short diffuse fibrils, whereas only mature amyloid fibrils were detected after one day of incubation. The aggregation was reduced when Abeta was incubated in the presence of Abeta ligands, oligopeptides previously shown to inhibit fibril formation, and aggregates were partly dissociated after the addition of the ligands.
The polymerization of Abeta is a highly cooperative process in which the formation of very large aggregates precedes the formation of fibrils. The entire process can be inhibited and, at least in early stages, partly reversed by Abeta ligands.
淀粉样β肽（Aβ）在脑实质和脑脊膜血管中形成纤维状沉积物是阿尔茨海默病发病机制中的关键步骤。在本报告中，使用荧光相关光谱法（FCS）研究了Aβ的聚合，该技术能够同时检测溶液中的小分子和大聚集体。
溶解于pH 7.4的Tris缓冲盐溶液中的Aβ在临界浓度50μM以上发生聚合，从单体/二聚体开始形成两个离散的大聚集体群体，未检测到任何寡聚体。聚集表现出非常高的协同性，40分钟后达到最大值，随后单体/二聚体数量增加，大聚集体尺寸减小。在最大聚集时制备的样品的电子显微镜照片显示为无定形网络和短扩散纤维的混合物，而孵育一天后仅检测到成熟的淀粉样纤维。当Aβ在Aβ配体存在下孵育时，聚集减少，Aβ配体是先前显示可抑制纤维形成的寡肽，添加配体后聚集体部分解离。
Aβ的聚合是一个高度协同的过程，其中非常大的聚集体的形成先于纤维的形成。整个过程可以被Aβ配体抑制，并且至少在早期可以部分逆转。
