Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity
Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity
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DOI：
10.1111/jnc.13514
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Glatzel, Markus
中科院分区：
文献类型：
--
作者：
Falker, Clemens;Hartmann, Alexander;Glatzel, Markus
阿尔茨海默病是一种常见的神经退行性、进行性和致命性疾病。淀粉样β（A）肽的产生和沉积与其发病机制相关，并且小的可溶性A寡聚体显示出最显著的神经毒性作用，并与疾病的发生和进展相关。最近的研究结果表明，A寡聚体结合细胞朊蛋白（PrPC）引起神经毒性作用。外泌体，内体起源的小细胞外囊泡，在阿尔茨海默病中的作用知之甚少。除了作为疾病的生物标志物，它们还可以促进A斑块的形成，减少A介导的突触毒性，并增强A清除。在这里，我们探讨了外泌体PrPC如何连接到阿尔茨海默病中归因于外泌体的保护功能。为了实现这一点，我们产生了小鼠神经母细胞瘤PrPC敲除细胞系使用转录激活因子样效应核酸酶。使用这些，以及SH-SY 5 Y人神经母细胞瘤细胞，我们表明，PrPC是高度富集的外泌体和外泌体结合淀粉样蛋白β通过PrPC。外泌体显示出对二聚体、五聚体和寡聚体A种类的最高结合亲和力。硫磺素T测定显示，外泌体PrPC加速淀粉样蛋白β的纤维化，从而减少寡聚体A赋予的神经毒性作用。我们的研究为外泌体在A介导的神经变性中的保护作用提供了进一步的证据，并强调了外泌体PrPC在阿尔茨海默病分子机制中的重要性。
Alzheimer's disease is a common neurodegenerative, progressive, and fatal disorder. Generation and deposition of amyloid beta (A) peptides associate with its pathogenesis and small soluble A oligomers show the most pronounced neurotoxic effects and correlate with disease initiation and progression. Recent findings showed that A oligomers bind to the cellular prion protein (PrPC) eliciting neurotoxic effects. The role of exosomes, small extracellular vesicles of endosomal origin, in Alzheimer's disease is only poorly understood. Besides serving as disease biomarkers they may promote A plaque formation, decrease A-mediated synaptotoxicity, and enhance A clearance. Here, we explore how exosomal PrPC connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrPC knockout cell line using transcription activator-like effector nucleases. Using these, as well as SH-SY5Y human neuroblastoma cells, we show that PrPC is highly enriched on exosomes and that exosomes bind amyloid beta via PrPC. Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric A species. Thioflavin T assays revealed that exosomal PrPC accelerates fibrillization of amyloid beta, thereby reducing neurotoxic effects imparted by oligomeric A. Our study provides further evidence for a protective role of exosomes in A-mediated neurodegeneration and highlights the importance of exosomal PrPC in molecular mechanisms of Alzheimer's disease.