Structural Basis of ß-Amyloid-Dependent Synaptic Dysfunctions
Structural Basis of ß-Amyloid-Dependent Synaptic Dysfunctions
复制标题
DOI：
10.1002/anie.201105638
复制
发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Faendrich, Marcus
中科院分区：
文献类型：
--
作者：
Haupt, Christian;Leppert, Joerg;Faendrich, Marcus
β-淀粉样蛋白（Aβ）肽聚集成寡聚体和原纤维是阿尔茨海默病（AD）的标志。[1]越来越多的证据表明，在AD的主要损害是由寡聚体的物种，损害突触网络的有序功能。[1]与此观点一致，寡聚体被证明影响突触可塑性，并且它们损害活脑组织中的长时程增强（LTP），这是脑记忆功能的广泛使用的模型系统。[1，2]使用固态NMR光谱，我们在此确定了高度突触毒性β淀粉样蛋白寡聚体结构的残基特异性分子构象。我们的测量揭示了一个稳定的N端β链，它控制着寡聚体和原纤维形成之间的分配，而靶向N端肽可以改善Aβ依赖性神经元功能障碍。目前研究的，化学上定义明确的Aβ寡聚体忠实地再现了AD相关寡聚体的标志性特征。将活海马脑切片暴露于不同的Aβ构象异构体（图1A），并施加一系列强直电刺激以引起突触传递的持久增加，称为LTP。低聚物，但不是新鲜溶解的，即主要是单体的Aβ肽或原纤维，降低了LTP反应，因此干扰了这些组织样本中的大脑记忆功能（图1B）。在培养的原代神经元中也观察到类似的寡聚体特异性，其表现出显著的寡聚体依赖性降低（约40%），
Aggregation of β-amyloid (Aβ) peptide into oligomers and protofibrils is a hallmark of Alzheimer s disease (AD).[1] Increasing evidence shows that the primary insult in AD is caused by oligomeric species that impair the ordered function of synaptic networks.[1] Consistent with this view, oligomers were shown to affect synaptic plasticity, and they impair the long-term potentiation (LTP) in living brain tissues, a widely used model system of brain memory functions.[1, 2] Using solidstate NMR spectroscopy, we here determined the residuespecific molecular conformation of a highly synaptotoxic βamyloid oligomer structure. Our measurements reveal a stable N-terminal β strand that controls the partitioning between oligomer and protofibril formation, whereas targeting the peptide N-terminus ameliorates Aβ-dependent neuronal dysfunctions.The presently investigated, chemically well-defined Aβ oligomers faithfully reproduce the hallmark characteristics of AD-related oligomers. Living hippocampal brain slices were exposed to different Aβ conformers (Figure 1 A), and a series of tetanic electrical stimuli were applied to evoke a longlasting increase of the synaptic transmission, termed LTP. Oligomers, but not freshly dissolved, that is, primarily monomeric, Aβ peptide or fibrils, reduce the LTP response and therefore disturb the brain memory functions within these tissue samples (Figure 1B). A similar oligomer-specificity is seen with cultured primary neurons, which present a significant oligomer-dependent decrease (À40%) of their