Mixtures of wild-type and a pathogenic (E22G) form of Aβ40 in vitro accumulate protofibrils, including amyloid pores
Mixtures of wild-type and a pathogenic (E22G) form of Aβ40 in vitro accumulate protofibrils, including amyloid pores
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DOI：
10.1016/s0022-2836(03)00927-6
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发表时间：
2003-09-26
影响因子：
5.6
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Lashuel, HA;Hartley, DM;Lansbury, PT
尽管与遗传性阿尔茨海默病（AD）相关的APP突变相对罕见，但对这些突变的详细研究可能对了解AD的机制和病因至关重要。在这里，我们提出了淀粉样蛋白（Abeta40(ARC)）北极变体（E22G）形成的原纤维结构特性的详细生物物理特征，以及Abeta40（WT）对Abeta40（ARC）形成的原纤维物种分布的影响，通过表征两种蛋白质的生物学相关混合物，可能模拟杂合患者的情况。这些研究表明，北极突变加速了体外β寡聚化和纤维形成。此外，Abeta40（ARC）对Abeta原纤维的形态和大小分布均有影响。电镜观察Abeta40（ARC）形成的原原纤维的形态包括：(1)相对致密的球形颗粒，直径约为4-5 nm；(2)环状孔状原纤维；(3)直径18 ~ 25nm的大球形颗粒；(4)具有链状形态的短花丝。与Abeta40(WT)/Abeta40（ARC）混合溶液中形成的原纤维相比，Abeta40（ARC）原纤维向原纤维的转化速度更快，这表明Abeta40（ARC）与Abeta40（WT）共孵育导致Abeta40（ARC）原纤维的动力学稳定。因此，在家族性阿尔茨海默病突变携带者中，Abeta(WT)/Abeta（MUT）比值的增加可能导致潜在神经毒性原纤维的积累和疾病进展的加速。(C) 2003 Elsevier Ltd.版权所有。
Although APP mutations associated with inherited forms of Alzheimer's disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-beta protein (Abeta40(ARC)) as well as the effect of Abeta40(WT) on the distribution of the protofibrillar species formed by Abeta40(ARC) by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Abeta oligomerization and fibrillogenesis in vitro. In addition, Abeta40(ARC) was observed to affect both the morphology and the size distribution of Abeta protofibrils. Electron microscopy examination of the protofibrils formed by Abeta40(ARC) revealed several morphologies, including: (1) relatively compact spherical particles roughly 4-5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical particles 18-25 nm in diameter; and (4) short filaments with chain-like morphology. Conversion of Abeta40(ARC) protofibrils to fibrils occurred more rapidly than protofibrils formed in mixed solutions of Abeta40(WT)/Abeta40(ARC), suggesting that co-incubation of Abeta40(ARC) with Abeta40(WT) leads to kinetic stabilization of Abeta40(ARC) protofibrils. An increase in the ratio of Abeta(WT)/Abeta(MUT(Arctic)), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers. (C) 2003 Elsevier Ltd. All rights reserved.