High-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer’s disease (rpAD). The current investigation aims at identifying interacting partners of HDPs in the rpAD brains to unravel the pathological involvement of HDPs in the rapid progression. HDPs from the frontal cortex tissues of rpAD brains were isolated using sucrose density gradient centrifugation. Proteins interacting with HDPs were identified by co-immunoprecipitation coupled with mass spectrometry. Further verifications were carried out using proteomic tools, immunoblotting, and confocal laser scanning microscopy. We identified rpAD-specific HDP-interactors, including the growth arrest specific 2-like 2 protein (G2L2). Intriguingly, rpAD-specific disturbances were found in the localization of G2L2 and its associated proteins i.e., the end binding protein 1, α-tubulin, and β-actin. The results show the involvement of HDPs in the destabilization of the neuronal actin/tubulin infrastructure. We consider this disturbance to be a contributing factor for the rapid progression in rpAD.

中文翻译：

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朊病毒蛋白寡聚体在快速进展的阿尔茨海默病中引起神经元细胞骨架损伤

先前已在快速进展的阿尔茨海默病 (rpAD) 患者的脑组织中发现朊病毒蛋白 (HDP) 的高密度寡聚体。目前的调查旨在确定 rpAD 大脑中 HDP 的相互作用伙伴，以解开 HDP 在快速进展中的病理参与。使用蔗糖密度梯度离心法从 rpAD 大脑的额叶皮层组织中分离出 HDP。与 HDP 相互作用的蛋白质通过免疫共沉淀结合质谱法进行鉴定。使用蛋白质组学工具、免疫印迹和共聚焦激光扫描显微镜进行了进一步验证。我们确定了 rpAD 特异性 HDP 相互作用物，包括生长停滞特异性 2 样 2 蛋白 (G2L2)。耐人寻味的是，在 G2L2 及其相关蛋白（即末端结合蛋白 1、α-微管蛋白和 β-肌动蛋白）的定位中发现了 rpAD 特异性干扰。结果表明 HDP 参与了神经元肌动蛋白/微管蛋白基础设施的不稳定。我们认为这种干扰是 rpAD 快速进展的一个促成因素。