Spreading of amyloid-p peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance
Spreading of amyloid-p peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance
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DOI：
10.1016/j.nbd.2013.12.019
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发表时间：
2014-05-01
影响因子：
6.1
通讯作者：
Nath, Sangeeta
中科院分区：
文献类型：
--
作者：
Domert, Jakob;Rao, Sahana Bhima;Nath, Sangeeta
病理通过神经元通路的扩散可能是阿尔茨海默病（AD）和其他神经退行性疾病中观察到的进行性认知丧失的原因。我们最近利用我们的供体-受体3-D共培养模型展示了寡聚淀粉样蛋白（A β）残基1-42 （oA β(1-42)）通过细胞间转移的AD病理学传播。我们现在表明，不同的A β -异构体（荧光标记的1- 42,3 (pE)-40, 1-40和11-42低聚物）可以从一个细胞转移到另一个细胞。因此，转移不限于特定的a β -异构体。尽管不同的A - β亚型可以转移，但清除和/或降解这些聚合亚型的能力的差异导致最终进入接收细胞的净量存在巨大差异，而净剩余的A - β可导致接收细胞中的播散和病理。这种细胞清除和/或降解的不足会导致易于聚集的A β(1-42)异构体在细胞内大量积聚，进一步促进细胞间转移；因此，oA β(1-42)是一种潜在的毒性亚型。此外，细胞间转移被证明是一个早期事件，似乎独立于细胞毒性的后期表现。这一现象可以解释阿尔茨海默病病理的种子如何在第一个细胞开始恶化之前传递到新的大脑区域并逐渐诱导阿尔茨海默病病理，以及细胞间转移如何与影响阿尔茨海默病发展中的细胞清除和/或降解的因素一起起作用。(C) 2014年作者。Elsevier Inc.出版。版权所有。
The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (A beta) residues 1-42 (oA beta(1-42)) using our donor-acceptor 3-D co-culture model. We now show that different A beta-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific A beta-isoform. Although different A beta isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining A beta can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone A beta(1-42) isoform, which further promotes cell-to-cell transfer; thus, oA beta(1-42) is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.