...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide
【24h】

Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide

机译：通过细胞摄取，浓缩和聚集淀粉样β肽形成的淀粉样种子

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

One of the neuropathological hallmarks of Alzheimer's disease (AD) is the amyloid plaque, primarily composed of aggregated amyloid-beta (Aβ) peptide. In vitro, Aβ_(1-42), the major alloform of Aβ found in plaques, self-assembles into fibrils at micromolar concentrations and acidic pH. Such conditions do not exist in the extracellular fluid of the brain where the pH is neutral and Aβ concentrations are in the nanomolar range. Here, we show that extracellular soluble Aβ (sAβ) at concentrations as low as 1 nM was taken up by murine cortical neurons and neuroblastoma (SHSY5Y) cells but not by human embryonic kidney (HEK293) cells. Following uptake, Aβ accumulated in Lysotracker-positive acidic vesicles (likely late endosomes or lyso-somes) where effective concentrations (>2.5 μM) were greater than two orders of magnitude higher than that in the extracellular fluid (25 nM), as quantified by fluorescence intensity using laser scanning confocal microscopy. Furthermore, SHSY5Y cells incubated with 1 μ_M Aβ_(1-42) for several days demonstrated a time-dependent increase in intracellular high molecular weight (HMW) (>200 kDa) aggregates, which were absent in cells grown in the presence of Aβ_(1-40). Homog-enates from these Aβ_(1-42)-loaded cells were capable of seeding amyloid fibril growth. These results demonstrate that Aβ can be taken up by certain cells at low physiologically relevant concentrations of extracellular Aβ, and then concentrated into endosomes/lysosomes. At high concentrations, vesicular Aβ aggregates to form HMW species which are capable of seeding amyloid fibril growth. We speculate that extrusion of these aggregates may seed extracellular amyloid plaque formation during AD pathogenesis.
机译：阿尔茨海默氏病（AD）的神经病理学标志之一是淀粉样斑块，主要由聚集的淀粉样β（Aβ）肽组成。在体外，斑块中发现的主要Aβ同种异形Aβ_（1-42）在微摩尔浓度和酸性pH下会自组装为原纤维。在pH为中性且Aβ浓度在纳摩尔范围内的大脑细胞外液中不存在这种情况。在这里，我们显示，鼠皮质神经元和神经母细胞瘤（SHSY5Y）细胞摄取了低至1 nM浓度的细胞外可溶性Aβ（sAβ），而人类胚胎肾（HEK293）细胞则没有。摄取后，Aβ累积在Lysotracker阳性酸性囊泡（可能是晚期内体或溶酶体）中，其有效浓度（> 2.5μM）比细胞外液（25 nM）中的浓度高两个数量级，通过使用激光扫描共聚焦显微镜检测荧光强度。此外，与1μMAβ_（1-42）孵育几天的SHSY5Y细胞显示出随时间增加的细胞内高分子量（HMW）（> 200 kDa）聚集体，而在存在Aβ_（ 1-40）。来自这些Aβ_（1-42）加载的细胞的同系物能够接种淀粉样原纤维的生长。这些结果表明，某些生理低浓度的细胞外Aβ可以吸收某些细胞中的Aβ，然后浓缩成内体/溶酶体。在高浓度下，囊泡Aβ聚集形成HMW物种，能够播种淀粉样原纤维生长。我们推测这些聚集体的挤出可能在AD发病机理中播种细胞外淀粉样斑块形成。

著录项

  • 来源
  • 作者

    Xiaoyan Hu; Scott L. Crick; Guojun Bu; Carl Frieden; Rohit V. Pappu; Jin-Moo Lee;

  • 作者单位

    Hope Center for Neurological Disorders and Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Biomedical Engineering and Center for Computational Biology, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Pediatrics, Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Biomedical Engineering and Center for Computational Biology, Washington University School of Medicine, St. Louis, MO 63110;

    Hope Center for Neurological Disorders and Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    amyloid fibrils; late endosomes; lysosomes; plaques;

    机译：淀粉样原纤维晚期内体溶酶体斑块;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号