Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
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DOI：
10.1073/pnas.0902640106
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发表时间：
2009-05-05
影响因子：
11.1
通讯作者：
Pepys, Mark B.
中科院分区：
文献类型：
--
作者：
Kolstoe, Simon E.;Ridha, Basil H.;Pepys, Mark B.
阿尔茨海默病的新的治疗方法是迫切需要的。正常血浆蛋白，血清淀粉样蛋白P组分（SAP），总是存在于脑脊液（CSF）和阿尔茨海默病的特异性病变、脑血管和脑内A β淀粉样蛋白斑和神经纤维缠结中，这是其分别与淀粉样蛋白原纤维和成对螺旋丝结合的结果。SAP本身也可能具有直接的神经细胞毒性。在此，在双（D-脯氨酸）化合物（R）-1-[6-[（R）-2-羧基-吡咯烷-1-基]-6-氧代-己酰基]吡咯烷-2-羧酸（CPHPC）在阿尔茨海默病中的这项独特研究中，我们观察到循环SAP的消耗以及SAP从CSF中的显著的、几乎完全的消失。我们证明，SAP消耗在体内引起的CPHPC交联对SAP分子在溶液中形成复合物，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，磷酸苏氨酸可能是过度磷酸化tau蛋白的配体。这些结果支持了在阿尔茨海默病和潜在的其他神经退行性疾病中SAP耗竭的进一步临床研究。
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 A beta 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 neurocytotoxic. 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 hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neuro-degenerative diseases.