Synergistic interactions between Alzheimer's Aβ40 and Aβ42 on the surface of primary neurons revealed by single molecule microscopy.
Synergistic interactions between Alzheimer's Aβ40 and Aβ42 on the surface of primary neurons revealed by single molecule microscopy.
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DOI：
10.1371/journal.pone.0082139
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gafni A
中科院分区：
文献类型：
--
作者：
Chang CC;Althaus JC;Carruthers CJ;Sutton MA;Steel DG;Gafni A
两种淀粉样β肽（Aβ40和Aβ42）在与阿尔茨海默病相关的细胞外脑沉积中具有显著特征。虽然Aβ40是脑脊液中的常见形式，但在疾病发展过程中，淀粉样蛋白沉积物中Aβ42的比例增加。Aβ寡聚体的低体内浓度（pM-nM）和亚稳态性质使得其大小、组成、细胞结合位点和作用机制的鉴定具有挑战性且难以实现。此外，最近的研究表明，Aβ40和Aβ42之间的协同效应改变了各种肽寡聚体的形成和稳定性以及它们的细胞毒性。这些研究通常使用在溶液中以μM肽浓度制备的Aβ寡聚体。目前的工作是使用生理Aβ浓度和单分子显微镜进行的，以跟踪肽结合和原代培养神经元上的缔合。当细胞暴露于nM Aβ40：Aβ42的1：1混合物时，与单独使用任一肽形成的寡聚体相比，形成了明显更大的膜结合寡聚体。单分子水平的荧光共振能量转移实验表明，这些较大的寡聚体含有Aβ40和Aβ42，但这些寡聚体的生长主要是通过添加Aβ42实现的。两种纯肽都形成很少的大于二聚体的寡聚体，但膜结合Aβ40/42复合物或Aβ40与Aβ42结合形成越来越大的寡聚体。这些发现可能解释了在生理条件下，Aβ42-显性寡聚体（被怀疑更具细胞毒性）如何在神经元膜上形成。
Two amyloid-β peptides (Aβ40 and Aβ42) feature prominently in the extracellular brain deposits associated with Alzheimer’s disease. While Aβ40 is the prevalent form in the cerebrospinal fluid, the fraction of Aβ42 increases in the amyloid deposits over the course of disease development. The low in vivo concentration (pM-nM) and metastable nature of Aβ oligomers have made identification of their size, composition, cellular binding sites and mechanism of action challenging and elusive. Furthermore, recent studies have suggested that synergistic effects between Aβ40 and Aβ42 alter both the formation and stability of various peptide oligomers as well as their cytotoxicity. These studies often utilized Aβ oligomers that were prepared in solution and at μM peptide concentrations. The current work was performed using physiological Aβ concentrations and single-molecule microscopy to follow peptide binding and association on primary cultured neurons. When the cells were exposed to a 1:1 mixture of nM Aβ40:Aβ42, significantly larger membrane-bound oligomers developed compared to those formed from either peptide alone. Fluorescence resonance energy transfer experiments at the single molecule level reveal that these larger oligomers contained both Aβ40 and Aβ42, but that the growth of these oligomers was predominantly by addition of Aβ42. Both pure peptides form very few oligomers larger than dimers, but either membrane bound Aβ40/42 complex, or Aβ40, bind Aβ42 to form increasingly larger oligomers. These findings may explain how Aβ42-dominant oligomers, suspected of being more cytotoxic, develop on the neuronal membrane under physiological conditions.
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DOI：
10.1016/j.bbadis.2008.06.003
发表时间：
2008-09-01
影响因子：
6.2
作者：
Chafekar, Sidhartha M.;Baas, Frank;Scheper, Wiep
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
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通讯作者：
WONG, CW
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
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影响因子：
2.4
作者：
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