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首页> 外文期刊>Biochemistry >Two Disaccharides and Trimethylamine N-Oxide Affect Aβ Aggregation Differently,but All Attenuate Oligomer-Induced Membrane Permeability
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Two Disaccharides and Trimethylamine N-Oxide Affect Aβ Aggregation Differently,but All Attenuate Oligomer-Induced Membrane Permeability

机译：两种二糖和三甲胺N-氧化物对Aβ聚集的影响不同，但均减弱了低聚物诱导的膜通透性

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Interaction between aggregates of amyloid beta protein (Aβ) and membranes has beennhypothesized by many to be a key event in the mechanism of neurotoxicity associated with Alzheimer’sndisease (AD). Proposed membrane-related mechanisms of neurotoxicity include ion channel formation,nmembrane disruption, changes inmembrane capacitance, and lipidmembrane oxidation.Recently, osmolytesnsuch as trehalose have been found to delay Aβ aggregation in vitro and reduce neurotoxicity. However, nondirect measurements have separated the effects of osmolytes on Aβ aggregation versus membrane interac-ntions. In this article, we tested the influence of trehalose, sucrose and trimethylamine-N-oxide (TMAO) on Aβnaggregation and fluorescent dye leakage induced by Aβ aggregates from liposomes. In the absence of lipidnvesicles, trehalose and sucrose, but not TMAO, were found to delay Aβ aggregation. In contrast, all of thenosmolytes significantly attenuated dye leakage. Dissolution of preformed Aβ aggregates was excluded as anpossible mechanism of dye leakage attenuation by measurements of Congo red binding as well as hydrogen-ndeuterium exchange detected by mass spectrometry (HX-MS). However, the accelerated conversion of highnorder oligomers to fibril caused by vesicles did not take place if any of the three osmolytes presented. Instead,nin the case of disaccharide, osmolytes were found to form adducts with Aβ, and change the dissociationndynamics of soluble oligomeric species. Both effects may have contributed to the observed osmolytenattenuation of dye leakage. These results suggest that disaccharides and TMAO may have very differentneffects on Aβ aggregation because of the different tendencies of the osmolytes to interact with the peptidenbackbone. However, the effects on Aβ membrane interaction may be due to much more general phenomenanassociated with osmolyte enhancement of Aβ oligomer stability and/or direct interaction of osmolyte with thenmembrane surface.
机译：许多人都认为淀粉样β蛋白（Aβ）聚集体与膜之间的相互作用是与阿尔茨海默氏症（AD）相关的神经毒性机制中的关键事件。拟议的与膜相关的神经毒性机制包括离子通道形成，膜破坏，膜电容变化和脂质膜氧化。最近，发现诸如海藻糖的渗透液可延迟体外Aβ聚集并降低神经毒性。然而，非直接测量已将渗透压剂对Aβ聚集与膜相互作用的影响分开。在本文中，我们测试了海藻糖，蔗糖和三甲胺-N-氧化物（TMAO）对脂质体中Aβ聚集体诱导的Aβ聚集和荧光染料渗漏的影响。在没有脂泡的情况下，发现海藻糖和蔗糖而不是TMAO会延迟Aβ聚集。相反，所有的渗渗物显着减弱了染料渗漏。通过测量刚果红结合以及通过质谱（HX-MS）检测到的氢-氘交换，排除了预先形成的Aβ聚集体的溶解是染料泄漏减弱的可能机制。但是，如果存在三种渗透压剂中的任何一种，则不会发生由囊泡引起的高阶低聚物加速转化为原纤维的现象。相反，在二糖的情况下，发现渗透液与Aβ形成加合物，并改变了可溶性寡聚体的离解动力学。两种作用都可能有助于观察到的染料渗渗渗透压减弱。这些结果表明，由于渗透物与肽骨干相互作用的趋势不同，二糖和TMAO对Aβ聚集的影响可能非常不同。然而，对Aβ膜相互作用的影响可能是由于与渗透压增强Aβ低聚物稳定性和/或渗透压与膜表面直接相互作用有关的更普遍的现象。

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  • 来源
    《Biochemistry》 |2009年第37期|p.8908-8919|共12页
  • 作者

    Wei Qi Aming Zhang Theresa A. Good and Erik J. Fernandez*;

  • 作者单位

    ‡Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904, and §Department of Chemical andBiochemical Engineering, University of Maryland Baltimore County, Baltimore, Maryland 21250;

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