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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
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Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component

机译：耗竭血清淀粉样蛋白P成分的阿尔茨海默氏病神经病理学分子解剖

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摘要

New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Aβ amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocyto-toxic. Here, in this unique study in Alzheimer's disease of the bis(D-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphos-phorylated τ protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neuro-degenerative diseases.
机译：迫切需要新的治疗阿尔茨海默氏病的方法。正常血浆蛋白，血清淀粉样蛋白P成分（SAP）始终存在于脑脊液（CSF）和阿尔茨海默氏病，脑血管和脑内Aβ淀粉样斑块以及神经原纤维缠结的病理性病变中，这是由于其与淀粉样蛋白原纤维结合和分别成对的螺旋丝。 SAP本身也可能直接具有神经细胞毒性。在这项关于双（D-脯氨酸）化合物的阿尔茨海默氏病的独特研究中，（R）-1- [6-[（R）-2-羧基-吡咯烷基-1-基] -6-氧代己酰基]吡咯烷-2-羧酸（CPHPC），我们观察到循环中的SAP耗竭，并且从CSF中SAP也消失了，几乎完全消失。我们证明了体内SAP耗竭是由CPHPC在溶液中形成的SAP分子交联对形成的，该复合物立即从血浆中清除。我们还解决了SAP与磷酸苏氨酸复合的结构，磷酸苏氨酸可能是高磷酸化τ蛋白上的配体。这些结果支持了SAP耗竭在阿尔茨海默氏病和其他潜在的神经退行性疾病中的进一步临床研究。

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  • 作者

    Simon E. Kolstoe; Basil H. Ridha; Vittorio Bellotti; Nan Wang; Carol V. Robinson; Sebastian J. Crutch; Geoffrey Keir; Riitta Kukkastenvehmas; J. Ruth Gallimore; Winston L. Hutchinson; Philip N. Hawkins; Stephen P. Wood; Martin N. Rossor; Mark B. Pepys; Mark B. Pepys;

  • 作者单位

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Dementia Research Centre, Department of Neurodegeneration, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom Dipartimento di Biochimica, Universita di Pavia, 27100 Pavia, Italy;

    Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom Argenta Discovery Ltd., Harlow, Essex CM19 5TR, United Kingdom;

    Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;

    Dementia Research Centre, Department of Neurodegeneration, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom;

    Dementia Research Centre, Department of Neuroinflammation, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom;

    Dementia Research Centre, Department of Neurodegeneration, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Dementia Research Centre, Department of Neurodegeneration, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

    Centre for Amyloidosis and Acute Phase Proteins and the National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom;

  • 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

    bis(D-proline); clinical study; neurodegenerative disease;

    机译：二（D-脯氨酸）;临床研究;神经退行性疾病;

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