Physiochemical characterization of the Alzheimer's disease-related peptides Aβ1-42Arctic and Aβ1-42wt
Physiochemical characterization of the Alzheimer's disease-related peptides Aβ1-42Arctic and Aβ1-42wt
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DOI：
10.1111/j.1742-4658.2006.05263.x
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发表时间：
2006-06-01
期刊：
影响因子：
5.4
通讯作者：
Lannfelt, Lars
中科院分区：
文献类型：
--
作者：
Johansson, Ann-Sofi;Berglind-Dehlin, Fredrik;Lannfelt, Lars
淀粉样β肽（A β）是阿尔茨海默病发病机制的关键。单体A β聚集成不溶性淀粉样蛋白原纤维通过几种可溶性A β中间体进行，包括原纤维，其被认为是疾病过程的中心。其主要原因是它们与具有北极淀粉样前体蛋白突变（E693 G）的家族性阿尔茨海默病有关。该突变引起早发性阿尔茨海默病，并且合成的A β 1- 40 Arctic在体外显示出增强的原纤维形成速率[Nilsberth C，Westlind-Danielsson A，Eckman CB，Condron MM，Axelman K，Forsell C，Stenh C，Luthman J，Teplow DB，Younkin SG，Naslund J & Lannfelt L.等（2001）Nat Neurosci 4，887-893]。为了增加我们对A β聚集所涉及的机制的理解，特别是A β单体寡聚成原纤维和原纤维纤维化成原纤维，在不同的生理化学条件下，如浓度、温度、离子强度和pH，检查了A β 1- 42 wt和A β 1- 42 Arctic聚集的动力学。我们使用尺寸排阻色谱法用于此目的，其中单体与原纤维分离，原纤维在离心步骤中与原纤维分离。北极突变显著加速A β 1- 42 wt原纤维形成和原纤维纤维化。此外，我们证明了两种不同的化学过程-单体寡聚化和原纤维纤维化-受到微环境变化的不同影响，并且北极突变改变了对这种变化的肽反应。
The amyloid beta peptide (A beta) is crucial for the pathogenesis of Alzheimer's disease. Aggregation of monomeric A beta into insoluble amyloid fibrils proceeds through several soluble A beta intermediates, including protofibrils, which are believed to be central in the disease process. The main reason for this is their implication in familial Alzheimer's disease with the Arctic amyloid precursor protein mutation (E693G). This mutation gives rise to early onset Alzheimer's disease, and synthetic A beta 1-40Arctic displays an enhanced rate of protofibril formation in vitro[Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J & Lannfelt L. (2001) Nat Neurosci4, 887-893]. To increase our understanding of the mechanisms involved in A beta aggregation, especially A beta monomer oligomerization into protofibrils and protofibril fibrillization into fibrils, the kinetics of A beta 1-42wt and A beta 1-42Arctic aggregation were examined under different physiochemical conditions, such as concentration, temperature, ionic strength and pH. We used size exclusion chromatography for this purpose, where monomers are separated from protofibrils, and fibrils are separated from protofibrils in a centrifugation step. The Arctic mutation significantly accelerated both A beta 1-42wt protofibril formation and protofibril fibrillization. In addition, we demonstrated that two distinct chemical processes - monomer oligomerization and protofibril fibrillization - were affected differently by changes in the micro-environment and that the Arctic mutation alters the peptide response to such changes.