期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 18, 页码 7619-7623出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0902640106
关键词
bis(D-proline); clinical study; neurodegenerative disease
资金
- Medical Research Council Program [G97900510]
- Walters Kundert Trust
- Royal Society
- Alzheimer Research Trust
- United Kingdom Department of Health's National Institute for Health Research Biomedical Research Centres
- MRC [G7900510] Funding Source: UKRI
- Medical Research Council [G7900510] Funding Source: researchfish
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.
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