MRC Prion Unit at UCL, UCL Institute of Prion Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
MRC Prion Unit at UCL, UCL Institute of Prion Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
Open Biol. 2017 Nov;7(11). doi: 10.1098/rsob.170158.
Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP). Ligands that bind to PrP can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP and emphasize the bidirectional nature of the interplay between Aβ and PrP in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common.
朊病毒导致致命的神经退行性疾病，如克雅氏病（CJD），由错误折叠的细胞朊蛋白（PrP）的多链组装体组成。与 PrP 结合的配体可以抑制朊病毒的传播和神经毒性。先前的大量研究已经确定，某些与阿尔茨海默病（AD）相关的淀粉样β-蛋白（Aβ）的可溶性组装体可以与 PrP 紧密结合，并且这种相互作用可能与它们在 AD 中的毒性有关。在这里，我们研究了这种可溶性 Aβ 组装体是否可能反过来对朊病毒的传播具有抑制作用。使用朊病毒感染和传播的细胞模型以及不同的 Aβ 制剂，我们发现与 PrP 结合最紧密的 Aβ 组装体形式也抑制了朊病毒的感染和传播。相比之下，与 PrP 结合能力弱或几乎没有结合能力的 Aβ 形式则无法减弱朊病毒的传播。这些数据表明，Aβ 的可溶性聚集体可以与朊病毒竞争与 PrP 的结合，并强调了 Aβ 和 PrP 之间在阿尔茨海默病和朊病毒病中的相互作用的双向性质。Aβ 对朊病毒传播的这种抑制作用可能有助于解释在常见脑 Aβ 沉积的高龄人群中散发性 CJD 的发病率明显下降的现象。
