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Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.

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 Abeta 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 neurodegenerative diseases.
AuthorsSimon 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
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 18 Pg. 7619-23 (May 05 2009) ISSN: 1091-6490 [Electronic] United States
PMID19372378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carboxylic Acids
  • Pyrrolidines
  • R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid
  • Serum Amyloid P-Component
Topics
  • Alzheimer Disease (blood, cerebrospinal fluid, metabolism)
  • Carboxylic Acids (administration & dosage)
  • Circular Dichroism
  • Crystallography, X-Ray
  • Humans
  • Mass Spectrometry
  • Middle Aged
  • Pilot Projects
  • Protein Conformation
  • Pyrrolidines (administration & dosage)
  • Serum Amyloid P-Component (antagonists & inhibitors, cerebrospinal fluid, chemistry)

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