Conformational Dynamics of Specific Aβ Oligomers Govern Their Ability To Replicate and Induce Neuronal Apoptosis.
Conformational Dynamics of Specific Aβ Oligomers Govern Their Ability To Replicate and Induce Neuronal Apoptosis.
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DOI：
10.1021/acs.biochem.6b00161
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发表时间：
2016-04-19
期刊：
影响因子：
2.9
通讯作者：
Rangachari V
中科院分区：
文献类型：
--
作者：
Dean DN;Pate KM;Moss MA;Rangachari V
淀粉样蛋白-β (Aβ)低聚物被认为是阿尔茨海默病（AD）早期突触功能障碍和神经元死亡的主要毒性物质。表征低聚物是描述AD发病机制复杂分子机制的重要一步。在我们之前的报告中，我们确定了a β42的一种独特的12 - 24聚神经毒性低聚物，称为大脂肪酸衍生低聚物（LFAOs），具有独特的复制特性，其中LFAOs在与单体相互作用时直接复制到定量较大的数量。这种自我复制的过程有点像朊病毒的复制。在本报告中，我们试图研究LFAOs所经历的浓度依赖性构象动力学，以及这种转变如何在其复制和诱导神经元凋亡的能力中表现出来。结果表明，LFAOs在12-24mers和12-24mers之间发生了浓度依赖的转移，解离常数（Kd）为0.1 μM。这两个物种的不同之处在于它们各自的三级结构，而不是二级结构。LFAOs的这种构象动力学与其在SH-SY5Y人神经母细胞瘤细胞中复制和诱导凋亡的能力相关，其中12mers比12-24mers更具有神经毒性，更容易复制。后一个结果暗示自繁殖复制过程在低生理浓度下占主导地位。本报告的观察结果可能对破译Aβ寡聚物表型的难以捉摸的作用以及确定它们在AD病理中的朊病毒型行为具有深远的意义。
Oligomers of amyloid-β (Aβ) have emerged as the primary toxic agents responsible for early synaptic dysfunction and neuronal death in Alzheimer disease (AD). Characterization of oligomers is an important step in the progress towards delineating the complex molecular mechanisms involved in AD pathogenesis. In our previous reports, we established that a distinct 12–24mer neurotoxic oligomer of Aβ42, called Large Fatty Acid derived Oligomers (LFAOs), exhibits a unique property of replication in which LFAOs directly duplicate to quantitatively larger amounts upon interacting with monomers. This self-propagative process of replication is somewhat reminiscent of prion propagation. In this report, we sought to investigate the concentration-dependent conformational dynamics LFAOs undergo and how such transitions manifest in their ability to replicate and induce neuronal apoptosis. The results indicate that LFAOs undergo a concentration-dependent transition between 12mers and disperse 12–24mers with a dissociation constant (Kd) of 0.1 μM. The two species differ in their respective tertiary structures but not their secondary structures. This conformational dynamics of LFAOs correlates with their ability to replicate and to induce apoptosis in SH-SY5Y human neuroblastoma cells, with 12mers being more neurotoxic and prone to replication than 12–24mers. The latter result implicates the self-propagating replication process to dominate at low physiological concentrations. The observations made in this report may have profound significance in deciphering the elusive roles of Aβ oligomer phenotypes and in determining their prion-type behavior in AD pathology.