Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064.
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28625-28631. doi: 10.1073/pnas.2009238117. Epub 2020 Nov 2.
Evidence linking amyloid beta (Aβ) cellular uptake and toxicity has burgeoned, and mechanisms underlying this association are subjects of active research. Two major, interconnected questions are whether Aβ uptake is aggregation-dependent and whether it is sequence-specific. We recently reported that the neuronal uptake of Aβ depends significantly on peptide chirality, suggesting that the process is predominantly receptor-mediated. Over the past decade, the cellular prion protein (PrP) has emerged as an important mediator of Aβ-induced toxicity and of neuronal Aβ internalization. Here, we report that the soluble, nonfibrillizing Aβ (1-30) peptide recapitulates full-length Aβ stereoselective cellular uptake, allowing us to decouple aggregation from cellular, receptor-mediated internalization. Moreover, we found that Aβ (1-30) uptake is also dependent on PrP expression. NMR-based molecular-level characterization identified the docking site on PrP that underlies the stereoselective binding of Aβ (1-30). Our findings therefore identify a specific sequence within Aβ that is responsible for the recognition of the peptide by PrP, as well as PrP-dependent cellular uptake. Further uptake stereodifferentiation in PrP-free cells points toward additional receptor-mediated interactions as likely contributors for Aβ cellular internalization. Taken together, our results highlight the potential of targeting cellular surface receptors to inhibit Aβ cellular uptake as an alternative route for future therapeutic development for Alzheimer's disease.
已有大量证据表明细胞摄取淀粉样β（Aβ）与毒性之间存在关联，而这一关联的机制是当前研究的热点。有两个主要的、相互关联的问题，一是 Aβ 的摄取是否依赖于聚集，二是是否具有序列特异性。我们最近的研究报告表明，神经元对 Aβ 的摄取在很大程度上依赖于肽的手性，这表明该过程主要是受体介导的。在过去的十年中，细胞朊蛋白（PrP）已成为 Aβ 诱导毒性和神经元内 Aβ 内化的重要介质。在这里，我们报告可溶性、非纤维状的 Aβ（1-30）肽重现了全长 Aβ 的立体选择性细胞摄取，使我们能够将聚集与细胞受体介导的内化分离。此外，我们发现 Aβ（1-30）的摄取也依赖于 PrP 的表达。基于 NMR 的分子水平表征确定了 PrP 上的对接位点，该位点是 Aβ（1-30）立体选择性结合的基础。因此，我们的研究结果确定了 Aβ 中负责识别肽的特定序列，以及 PrP 依赖的细胞摄取。在没有 PrP 的细胞中进一步的摄取立体差异表明，其他受体介导的相互作用可能是 Aβ 细胞内化的原因。总之，我们的研究结果强调了靶向细胞表面受体抑制 Aβ 细胞摄取作为阿尔茨海默病未来治疗发展的替代途径的潜力。
