Department of CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse, Biberach an der Riss D-88397, Germany.
Biochemistry. 2013 Feb 26;52(8):1466-76. doi: 10.1021/bi3016444. Epub 2013 Feb 14.
In Alzheimer's disease, substantial evidence indicates the causative role of soluble amyloid β (Aβ) aggregates. Although a variety of Aβ assemblies have been described, the debate about their individual relevance is still ongoing. One critical issue hampering this debate is the use of different methods for the characterization of endogenous and synthetic peptide and their intrinsic limitations for distinguishing Aβ aggregates. Here, we used different protocols for the establishment of prefibrillar Aβ assemblies with varying morphologies and sizes and compared them in a head-to-head fashion. Aggregation was characterized via the monomeric peptide over time until spheroidal, protofibrillar, or fibrillar Aβ aggregates were predominant. It could be shown that a change in the ionic environment induced a structural rearrangement, which consequently confounds the delineation of a measured neurotoxicity toward a distinct Aβ assembly. Here, neuronal binding and hippocampal neurotransmission were found to be suitable to account for the synaptotoxicity to different Aβ assemblies, based on the stability of the applied Aβ aggregates in these settings. In contrast to monomeric or fibrillar Aβ, different prefibrillar Aβ aggregates targeted neurons and impaired hippocampal neurotransmission with nanomolar potency, albeit by different modalities. Spheroidal Aβ aggregates inhibited NMDAR-dependent long-term potentiation, as opposed to protofibrillar Aβ aggregates, which inhibited AMPAR-dominated basal neurotransmission. In addition, a provoked structural conversion of spheroidal to protofibrillar Aβ assemblies resulted in a time-dependent suppression of basal neurotransmission, indicative of a mechanistic switch in synaptic impairment. Thus, we emphasize the importance of addressing the metastability of prefacto characterized Aβ aggregates in assigning a biological effect.
在阿尔茨海默病中，大量证据表明可溶性淀粉样β（Aβ）聚集体起致病作用。尽管已经描述了多种 Aβ 组装体，但关于它们各自相关性的争论仍在继续。阻碍这一争论的一个关键问题是用于描述内源性和合成肽的不同方法的使用及其用于区分 Aβ 聚集体的固有局限性。在这里，我们使用了不同的方案来建立具有不同形态和大小的原纤维前 Aβ 组装体，并将它们进行了直接比较。通过单体肽随时间的聚合来进行聚集的特征分析，直到形成球形、原纤维或纤维状 Aβ 聚集体。结果表明，离子环境的变化会引起结构重排，从而混淆了对特定 Aβ 组装体的可测量神经毒性的划分。在这里，发现神经元结合和海马神经传递可用于解释不同 Aβ 组装体的突触毒性，这是基于在这些条件下应用的 Aβ 聚集体的稳定性。与单体或纤维状 Aβ 不同，不同的原纤维前 Aβ 聚集体以纳摩尔的效力靶向神经元并损害海马神经传递，尽管其作用模式不同。球形 Aβ 聚集体抑制了 NMDAR 依赖性长时程增强，而原纤维状 Aβ 聚集体则抑制了 AMPAR 主导的基础神经传递。此外，球形到原纤维状 Aβ 组装体的结构转换会导致基础神经传递的时间依赖性抑制，表明突触损伤的机制发生了变化。因此，我们强调在确定生物学效应时，解决预先特征化的 Aβ 聚集体的亚稳性的重要性。
