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

被引：59

作者：

Kolstoe, Simon E. ^{[1
,2
]}

Ridha, Basil H. ^{[4
]}

Bellotti, Vittorio ^{[1
,2
]}

Wang, Nan ^{[5
]}

Robinson, Carol V. ^{[5
]}

Crutch, Sebastian J. ^{[4
]}

Keir, Geoffrey ^{[3
]}

Kukkastenvehmas, Riitta ^{[4
]}

Gallimore, J. Ruth ^{[1
,2
]}

Hutchinson, Winston L. ^{[1
,2
]}

Hawkins, Philip N. ^{[1
,2
]}

Wood, Stephen P. ^{[1
,2
]}

Rossor, Martin N. ^{[4
]}

Pepys, Mark B. ^{[1
,2
]}

机构：

[1] UCL, Sch Med, Ctr Amyloidosis & Acute Phase Prot, London NW3 2PF, England

[2] UCL, Sch Med, Div Med, Natl Amyloidosis Ctr, London NW3 2PF, England

[3] UCL, Sch Med, Inst Neurol, Dept Neuroinflammat, London WC1N 3BG, England

[4] UCL, Sch Med, Dept Neurodegenerat, Dementia Res Ctr, London WC1N 3BG, England

[5] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 18期

基金：

英国医学研究理事会;

关键词：

bis(D-proline); clinical study; neurodegenerative disease; C-REACTIVE PROTEIN; BLOOD-BRAIN-BARRIER; IN-VITRO; CEREBROSPINAL-FLUID; DEPOSITS; IMMUNOREACTIVITY; PENTRAXINS; PEPTIDE; TAU; CSF;

D O I：

10.1073/pnas.0902640106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：7619 / 7623

页数：5

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