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

Kolstoe, SE; Ridha, BH; Bellotti, V; Wang, N; Robinson, CV; Crutch, SJ; Keir, G; ... Pepys, MB; + view all (2009) Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component. P NATL ACAD SCI USA , 106 (18) 7619 - 7623. 10.1073/pnas.0902640106.

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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 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.

Type: Article
Title: Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
DOI: 10.1073/pnas.0902640106
Keywords: bis(D-proline), clinical study, neurodegenerative disease, C-REACTIVE PROTEIN, BLOOD-BRAIN-BARRIER, IN-VITRO, CEREBROSPINAL-FLUID, DEPOSITS, IMMUNOREACTIVITY, PENTRAXINS, PEPTIDE, TAU, CSF
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/134851
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