Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity
Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity
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DOI：
10.1074/jbc.c112.400614
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发表时间：
2012-09-28
影响因子：
4.8
通讯作者：
Surewicz, Witold K.
中科院分区：
文献类型：
--
作者：
Nieznanski, Krzysztof;Choi, Jin-Kyu;Surewicz, Witold K.
阿尔茨海默病的发病机制似乎与淀粉样蛋白β（A β）肽的聚集，特别是可溶性A β 1-42寡聚体的形成密切相关。最近证实，细胞朊病毒蛋白PrPC以高亲和力结合这些寡聚体，充当介导至少一些它们的神经毒性作用的推定受体。在这里，我们表明，可溶性（即glycophosphatidylinositol anchorfree）朊病毒蛋白及其N-末端片段有很强的影响A β 1-42的聚集途径，抑制其组装成淀粉样纤维。此外，朊病毒蛋白防止通常在A β纤维形成期间发生的球形寡聚体的形成，如在神经元细胞培养实验中评估的，作为A β 1-42毒性的有效抑制剂。这些发现可能提供了一个分子水平的基础，以解释报告的生理释放的N-末端N1片段的PrPC对A β神经毒性的保护作用。他们还提出了一种新的方法来药物干预阿尔茨海默病。
The pathogenesis of Alzheimer disease appears to be strongly linked to the aggregation of amyloid-beta (A beta) peptide and, especially, formation of soluble A beta 1-42 oligomers. It was recently demonstrated that the cellular prion protein, PrPC, binds with high affinity to these oligomers, acting as a putative receptor that mediates at least some of their neurotoxic effects. Here we show that the soluble (i.e. glycophosphatidylinositol anchorfree) prion protein and its N-terminal fragment have a strong effect on the aggregation pathway of A beta 1-42, inhibiting its assembly into amyloid fibrils. Furthermore, the prion protein prevents formation of spherical oligomers that normally occur during A beta fibrillogenesis, acting as a potent inhibitor of A beta 1-42 toxicity as assessed in experiments with neuronal cell culture. These findings may provide a molecular level foundation to explain the reported protective action of the physiologically released N-terminal N1 fragment of PrPC against A beta neurotoxicity. They also suggest a novel approach to pharmacological intervention in Alzheimer disease.