Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
Biochem Biophys Res Commun. 2021 Jun 11;557:122-126. doi: 10.1016/j.bbrc.2021.03.174. Epub 2021 Apr 14.
Formation of amyloid oligomers and fibrils underlies the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's. One mechanism of action by which Aβ aggregates cause neuronal toxicity is through interactions with cellular membranes. Aβ aggregates have been shown to disrupt membrane integrity via pore formation, membrane thinning, or lipid extraction. At the same time, lipid membranes also affect the rate of Aβ aggregation and remodel pre-formed Aβ fibrils. Here we show that Aβ42 globulomers, a type of well-characterized and stable Aβ oligomers, convert to amyloid fibrils in the presence of DOPC liposomes. Electron paramagnetic resonance studies show that the fibrils converted from Aβ42 globulomers adopt the same structure as fibrils formed directly from monomers. Our results suggest that the interactions between Aβ oligomers and cellular membranes are dynamic. By converting Aβ oligomers to fibrils, the lipid membrane can reduce the membrane-disrupting activities caused by these oligomers. Modulation of Aβ-membrane interactions as a therapeutic strategy should take into account the dynamic nature of these interactions.
淀粉样寡聚体和纤维的形成是许多神经退行性疾病（如阿尔茨海默病）发病机制的基础。Aβ 聚集物引起神经元毒性的作用机制之一是与细胞膜相互作用。已经表明 Aβ 聚集物通过形成孔、膜变薄或脂质提取来破坏膜完整性。与此同时，脂质膜也会影响 Aβ 聚集的速度，并重塑预先形成的 Aβ 纤维。在这里，我们表明 Aβ42 球状体，一种具有良好特征和稳定的 Aβ 寡聚体，在 DOPC 脂质体存在下转化为淀粉样纤维。电子顺磁共振研究表明，从 Aβ42 球状体转化而来的纤维采用与直接从单体形成的纤维相同的结构。我们的结果表明，Aβ 寡聚体与细胞膜之间的相互作用是动态的。通过将 Aβ 寡聚体转化为纤维，脂质膜可以降低这些寡聚体引起的膜破坏活性。作为一种治疗策略，调节 Aβ-膜相互作用应该考虑到这些相互作用的动态性质。
