Department of Neurology, Medical Center - University of Freiburg, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Brain Pathol. 2020 Jan;30(1):36-45. doi: 10.1111/bpa.12734. Epub 2019 Jun 5.
Aggregation of amyloid-β (Aβ) that leads to the formation of plaques in Alzheimer's disease (AD) occurs through the stepwise formation of oligomers and fibrils. An earlier onset of aggregation is obtained upon intracerebral injection of Aβ-containing brain homogenate into human APP transgenic mice that follows a prion-like seeding mechanism. Immunoprecipitation of these brain extracts with anti-Aβ oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aβ deposition was still evident. Here, we establish that, together with Aβ monomers, Aβ oligomers trigger the initial phase of Aβ seeding and that the depletion of oligomeric Aβ delays the aggregation process, leading to a transient reduction of seed-induced Aβ deposits. This work extends the current knowledge about the role of Aβ oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aβ aggregation in vivo. We conclude that Aβ oligomers are important for the early initiation phase of the seeding process.
淀粉样蛋白-β（Aβ）的聚集导致阿尔茨海默病（AD）中的斑块形成，是通过寡聚体和纤维的逐步形成发生的。通过将含有 Aβ 的脑匀浆脑内注射到具有淀粉样前体蛋白（APP）转基因的小鼠中，可以获得更早的聚集，这遵循一种类似朊病毒的引发机制。用抗 Aβ 寡聚体抗体对这些脑组织提取物进行免疫沉淀，或对接受者动物进行被动免疫，可消除观察到的引发活性，尽管诱导的 Aβ 沉积仍然明显。在这里，我们确定 Aβ 寡聚体与 Aβ 单体一起触发 Aβ 引发的初始阶段，并且寡聚 Aβ 的耗尽会延迟聚集过程，导致种子诱导的 Aβ 沉积的短暂减少。这项工作通过指出 Aβ 寡聚体在体内 Aβ 聚集引发中的作用，扩展了 Aβ 寡聚体在其细胞毒性性质之外的现有知识。我们得出结论，Aβ 寡聚体对于引发过程的早期起始阶段很重要。
