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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease
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Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

机译:对小鼠家族性丹麦痴呆症进行建模可支持阿尔茨海默氏病淀粉样假说的概念

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摘要

Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuro-inflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neu-ritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP3015 tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between β-amyloid (Aβ)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Ap peptides, the lack of codeposition of the two peptides in crosses between ADan- and Aβ-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.
机译:家族性丹麦痴呆症(FDD)是一种进行性神经退行性疾病,具有Dan-淀粉样蛋白(ADan)的脑沉积,神经炎症和神经原纤维缠结,其特征与阿尔茨海默氏病(AD)极为相似。我们已经生成了家族性丹麦痴呆的转基因(tg)小鼠模型,该模型在整个大脑中表现出ADan的年龄依赖性沉积,并伴有相关的淀粉样血管病,微出血,中性营养不良和神经炎症。 Tg小鼠在莫里斯水迷宫中受损,并且在野外表现出更高的焦虑感。当与TauP3015 tg小鼠杂交时,ADan积累会促进神经原纤维病变,在所有方面都类似于在沉积有β淀粉样蛋白(Aβ)的tg小鼠和TauP301S tg小鼠之间的杂交中观察到的Tau病变。尽管这些观察结果证明了与序列无关的ADan和Ap肽的下游病理生理机制是共享的,但在沉积ADan和Aβ的小鼠之间的杂交中缺少两种肽的共沉积也表明了该肽的区别性。我们的结果支持AD和相关痴呆的淀粉样蛋白假说的概念,并表明易于形成淀粉样蛋白的不同蛋白质可以驱动大脑中惊人的相似致病途径。

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    Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany Department of Pathology, University of Tuebingen, 72076 Tuebingen, Germany Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, 72076 Tuebingen, Germany;

    rnDepartment of Pathology, University of Tuebingen, 72076 Tuebingen, Germany;

    rnNathan Kline Institute, Orangeburg, New York, NY 10962;

    rnNew York University School of Medicine, New York, NY 10016;

    rnMedical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom;

    rnTokyo Institute of Psychiatry, 156-8585 Tokyo, Japan;

    rnDepartment of Cell Biology, Center of Research and Advanced Studies of the National Polytechnic Institute, CP 07360 Mexico City, Mexico;

    rnInstitute of Anatomy and Center for Integrative Human Physiology, University of Zuerich, and Human Movement Sciences, Swiss Federal Institute of Technology, CH-8057 Zuerich, Switzerland;

    rnNathan Kline Institute, Orangeburg, New York, NY 10962 New York University School of Medicine, New York, NY 10016;

    rnDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany German Center for Neurodegenerative Diseases, 72076 Tuebingen, Germany;

  • 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

    ADan; ABeta; tau; neurodegeneration; mouse model;

    机译:阿丹阿贝塔;知道;神经变性鼠标模型;

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