Ann Romney Center for Neurologic Diseases, Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Neuron. 2023 Jul 5;111(13):2012-2020.e4. doi: 10.1016/j.neuron.2023.04.007. Epub 2023 May 10.
Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.
淀粉样 β 蛋白（Aβ）的可溶性寡聚物已被定义为从阿尔茨海默病（AD）大脑的水性提取物中经过超速离心后的上清液中的聚集物，被认为是突触功能障碍的上游启动子，但对其结构知之甚少。我们现在报告了一个意外的发现，即在 AD 大脑的毒性高速上清液中存在 Aβ 纤维，这些纤维是通过在水性缓冲液中浸泡提取出来的。纤维似乎不是在制备过程中形成的，其通过 EM 的计数与 Aβ ELISA 定量相关。水性 Aβ 纤维的冷冻电镜结构与来自 sarkosyl 不溶性匀浆的结构相同。在水性提取物中，纤维被 lecanemab 标记，lecanemab 是一种针对 Aβ 聚集物的抗体，据报道可改善 AD 的认知结果。lecanemab 提供了对水性纤维毒性的保护。我们得出的结论是，纤维在 AD 大脑的水性提取物中含量丰富，并且与斑块中的纤维具有相同的结构。这些发现对 AD 的发病机制和药物设计具有重要意义。
