Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA.
J Alzheimers Dis. 2018;66(1):57-73. doi: 10.3233/JAD-171080.
Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer's disease symptoms. Human and animal model studies report that senile plaques contain a halo of AβO molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. Shear hypotheses in the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both AβO types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry.
淀粉样β寡聚物（AβO）被认为是导致阿尔茨海默病症状出现之前突触功能障碍的神经毒素。人体和动物模型研究报告称，老年斑周围存在 AβO 分子的光环。在斑块无斑块的区域中，寡聚物的分布数量要少得多。有研究表明，寡聚物从光环迁移到附近的突触，并被整合到突触前和突触后末端。从这些光环中提取并注射到动物模型中时，这两种类型的寡聚物具有两种不同的毒性。本文提出了一种基于剪切能的解释，以说明这些研究中的数据。本系列前三篇论文中的剪切假设被应用于解释水动力和产生的剪切模式如何解释两种 AβO 类型的空间分布，斑块颗粒附近明显的突触损失，以及不同毒性的可能原因。提出了一种基于剪切的机制，用于局部剪切激发的 Aβ分子优先迁移到突触间隙。研究表明，由斑块颗粒周围间质液强制分流产生的高能层流剪切负责在斑块周围形成 AβO。研究表明，在无斑块区域，由于围绕突触的剪切能较低，会产生另一种毒性不同的 AβO，通过神经元膜表面或通过局部剪切的 Aβ分子在突触进入处附近的突触小间隙中以类朊病毒样的方式进行播种，从而将 AβO 沉积在突触内。
