Ganzinger Kristina A, Narayan Priyanka, Qamar Seema S, Weimann Laura, Ranasinghe Rohan T, Aguzzi Adriano, Dobson Christopher M, McColl James, St George-Hyslop Peter, Klenerman David
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
Chembiochem. 2014 Nov 24;15(17):2515-21. doi: 10.1002/cbic.201402377. Epub 2014 Oct 7.
Oligomers of the amyloid-β peptide (Aβ) play a central role in the pathogenesis of Alzheimer's disease and have been suggested to induce neurotoxicity by binding to a plethora of cell-surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrP(C)) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrP(C) and that the species bound to PrP(C) are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oAβ-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways.
淀粉样β肽（Aβ）寡聚体在阿尔茨海默病的发病机制中起核心作用，并且有人提出它们通过与大量细胞表面受体结合来诱导神经毒性。然而，由Aβ42形成的大小和构象各异的寡聚体的异质混合物掩盖了与特定受体结合的寡聚体种类的本质。在这里，我们使用单分子成像来表征Aβ42寡聚体（oAβ42），并证实oAβ42与活神经元细胞上的细胞朊蛋白（PrP(C)）之间存在有争议的相互作用。我们的结果表明，在纳摩尔浓度下，oAβ42与PrP(C)相互作用，并且与PrP(C)结合的种类主要是小寡聚体（二聚体和三聚体）。因此，单分子生物物理研究有助于阐明受体介导的oAβ诱导神经毒性的潜在机制，并最终促进发现这些途径的新型抑制剂。
