Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
- Simon E. Kolstoea,1,
- Basil H. Ridhab,1,
- Vittorio Bellottia,2,
- Nan Wangc,3,
- Carol V. Robinsonc,
- Sebastian J. Crutchb,
- Geoffrey Keird,
- Riitta Kukkastenvehmasb,4,
- J. Ruth Gallimorea,
- Winston L. Hutchinsona,
- Philip N. Hawkinsa,
- Stephen P. Wooda,
- Martin N. Rossorb and
- Mark B. Pepysa,4
- aCentre 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;
- bDementia Research Centre, Department of Neurodegeneration, and
- dDepartment of Neuroinflammation, Institute of Neurology, University College London Medical School, London, WC1N 3BG, United Kingdom; and
- cDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom
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Communicated by David Weatherall, University of Oxford, Oxford, United Kingdom, March 19, 2009
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↵1S.E.K. and B.H.R. contributed equally to this work. (received for review January 22, 2009)
Abstract
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 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 τ protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.
Footnotes
- 4To whom correspondence should be addressed. E-mail: m.pepys{at}medsch.ucl.ac.uk
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Author contributions: S.E.K., B.H.R., V.B., N.W., C.V.R., S.J.C., G.K., P.N.H., S.P.W., M.N.R., and M.B.P. designed research; S.E.K., B.H.R., V.B., N.W., C.V.R., S.J.C., G.K., R.K., J.R.G., W.L.H., S.P.W., and M.N.R. performed research; M.B.P. contributed new reagents/analytic tools; M.B.P. analyzed data; and M.B.P. wrote the paper.
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↵2Present address: Dipartimento di Biochimica, Universitá di Pavia, 27100 Pavia, Italy.
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↵3Present address: Argenta Discovery Ltd., Harlow, Essex CM19 5TR, United Kingdom.
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Conflict of interest: M.B.P. is the inventor on patents related to SAP and CPHPC that are owned by Pentraxin Therapeutics Ltd., a University College London spinout company in which he, P.N.H., and S.P.W. have shares, which owns CPHPC.
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Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2W08).
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This article contains supporting information online at www.pnas.org/cgi/content/full/0902640106/DCSupplemental.
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Freely available online through the PNAS open access option.
