Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.
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.
Kolstoe
Simon E
SE
Centre for Amyloidosis and Acute Phase Proteins and National Amyloidosis Centre, Division of Medicine (Royal Free Campus), University College London Medical School, London NW3 2PF, United Kingdom.
Ridha
Basil H
BH
Bellotti
Vittorio
V
Wang
Nan
N
Robinson
Carol V
CV
Crutch
Sebastian J
SJ
Keir
Geoffrey
G
Kukkastenvehmas
Riitta
R
Gallimore
J Ruth
JR
Hutchinson
Winston L
WL
Hawkins
Philip N
PN
Wood
Stephen P
SP
Rossor
Martin N
MN
Pepys
Mark B
MB
D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D002264:Carboxylic Acids / Q000008:administration & dosage*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006801:Humans; D013058:Mass Spectrometry; D008875:Middle Aged; D010865:Pilot Projects; D011487:Protein Conformation; D011759:Pyrrolidines / Q000008:administration & dosage*; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000737:chemistry
D002264:Carboxylic Acids; D011759:Pyrrolidines; C455899:R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid; D000683:Serum Amyloid P-Component