Studies with Radiolabelled Serum Amyloid P Component Provide Evidence for Turnover and Regression of Amyloid Deposits In Vivo

1994 ◽  
Vol 87 (3) ◽  
pp. 289-295 ◽  
Author(s):  
Philip N. Hawkins
Keyword(s):  
Amyloid Fibrils ◽  
Specific Binding ◽  
Serum Amyloid ◽  
Poor Correlation ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

1. Quantitative scintigraphic and turnover studies, utilizing the specific binding affinity of serum amyloid P component for amyloid fibrils, have been developed as a tool for evaluating amyloid deposits in vivo. 2. Serial studies in over 300 patients have shown characteristic, diagnostic tissue distributions of amyloid in different types of amyloidosis. There is generally a poor correlation between quantity of amyloid and associated organ dysfunction. 3. Contrary to previous expectations, regression of amyloid has been demonstrated systematically for the first time: AA, AL and variant transthyretin-associated amyloid deposits often regress rapidly, and sometimes completely, if the supply of fibril protein precursors is substantially reduced.

Amyloidosis

2020 ◽  
pp. 2218-2234
Author(s):  
Mark B. Pepys ◽  
Philip N. Hawkins
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Polarized Light ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Amyloidosis is the clinical condition caused by extracellular deposition of amyloid in the tissues. Amyloid deposits are composed of amyloid fibrils, abnormal insoluble protein fibres formed by misfolding of their normally soluble precursors. About 30 different proteins can form clinically or pathologically significant amyloid fibrils in vivo as a result of either acquired or hereditary abnormalities. Small, focal, clinically silent amyloid deposits in the brain, heart, seminal vesicles, and joints are a universal accompaniment of ageing. Clinically important amyloid deposits usually accumulate progressively, disrupting the structure and function of affected tissues and lead inexorably to organ failure and death. There is no licensed treatment which can specifically clear amyloid deposits, but intervention which reduces the availability of the amyloid fibril precursor proteins can arrest amyloid accumulation and may lead to amyloid regression with clinical benefit. Pathology—amyloid fibrils bind Congo red dye producing pathognomonic green birefringence when viewed in high-intensity cross-polarized light, and the protein type can be identified by immunostaining or proteomic analysis. Amyloid deposits always contain a nonfibrillar plasma glycoprotein, serum amyloid P component, the universal presence of which is the basis for use of radioisotope-labelled serum amyloid P component as a diagnostic tracer. Clinicopathological correlation—amyloid may be deposited in any tissue of the body, including blood vessels walls and connective tissue matrix; clinical manifestations are correspondingly diverse. Identification of the amyloid fibril protein is always essential for appropriate clinical management. The specific types of amyloidosis covered in this chapter are reactive systemic (AA) amyloidosis, monoclonal immunoglobulin light chain (AL) amyloidosis, and hereditary systemic amyloidoses (including familial amyloid polyneuropathy).

scholarly journals Binding specificity of serum amyloid P component for the pyruvate acetal of galactose.

1984 ◽  
Vol 159 (4) ◽  
pp. 1058-1069 ◽  
Author(s):  
C R Hind ◽  
P M Collins ◽  
D Renn ◽  
R B Cook ◽  
D Caspi ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Binding Specificity ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Calcium Dependent ◽  
Protein Ligands ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Serum amyloid P component (SAP) is a normal plasma protein that is of interest because of its presence in amyloid deposits, its presence in normal human glomerular basement membrane, and its stable evolutionary conservation. It has calcium-dependent ligand-binding specificity for amyloid fibrils, fibronectin (Fn), C4-binding protein (C4bp), and agarose. Although the binding to agarose, a linear galactan hydrocolloid derived from some marine algae, is unlikely per se to be related to the physiological function of SAP, it does provide a model system in which to explore the precise ligand requirements of SAP. We report here that the amount of SAP from human, mouse, and plaice (Pleuronectes platessa L.) serum able to bind to agarose from different sources reflect precisely their pyruvate content. Methylation with diazomethane of the carboxyl groups in the pyruvate moiety of agarose completely abolishes SAP binding to agarose. The pyruvate in agarose exists as the 4,6-pyruvate acetal of beta-D-galactopyranose. We have therefore synthesized this galactoside, using a novel procedure, established its structure by analysis of its nuclear magnetic resonance spectra, and shown that it completely inhibits all known calcium-dependent binding reactions of SAP. The R isomer of the cyclic acetal, methyl 4,6-O-(1-carboxyethylidene)-beta-D-galactopyranoside (MO beta DG) was effective at millimolar concentration and was more potent than its noncyclic analogue, while pyruvate, D-galactose, and methyl beta-D-galactopyranoside were without effect. The autologous protein ligands of SAP presumably, therefore express a structural determinant(s) that stereochemically resembles MO beta DG. Availability of this specific, well-characterized, low molecular weight ligand for SAP should facilitate further investigation of the function of SAP and its role in physiological and pathophysiological processes.

scholarly journals Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo

Open Biology ◽  
2016 ◽  
Vol 6 (2) ◽  
pp. 150202 ◽  
Author(s):  
Raya Al-Shawi ◽  
Glenys A. Tennent ◽  
David J. Millar ◽  
Angela Richard-Londt ◽  
Sebastian Brandner ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P ◽  
Cerebrovascular Amyloid

Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro , contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming ‘Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)’ clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA.

scholarly journals Specific localization and imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component.

1988 ◽  
Vol 167 (3) ◽  
pp. 903-913 ◽  
Author(s):  
P N Hawkins ◽  
M J Myers ◽  
A A Epenetos ◽  
D Caspi ◽  
M B Pepys
Keyword(s):  
Serum Amyloid ◽  
C Reactive Protein ◽  
Amyloid P Component ◽  
Reactive Protein ◽  
Amyloid A ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Highly specific, high-resolution scintigraphic images of amyloid-laden organs in mice with experimentally induced amyloid A protein (AA) amyloidosis were obtained after intravenous injection of 123I-labeled serum amyloid P component (SAP). Interestingly, a much higher proportion (up to 40%) of the injected dose of heterologous human SAP localized to amyloid and was retained there than was the case with isologous mouse SAP, indicating that human SAP binds more avidly to mouse AA fibrils than does mouse SAP. Specificity of SAP localization was established by the failure of the related proteins, human C-reactive protein and Limulus C-reactive protein, to deposit significantly in amyloid and by the absence of human SAP deposition in nonamyloidotic organs. However, only partial correlations were observed between the quantity of SAP localized and two independent estimates, histology and RIA for AA of the amount of amyloid in particular organs. It is not clear which of the three methods used reflects better the extent or clinical significance of the amyloid deposits but in vivo localization of radiolabeled SAP, detectable and quantifiable by gamma camera imaging, is apparently extremely sensitive. These findings establish the use of labeled SAP as a noninvasive in vivo diagnostic probe in experimental amyloidosis, potentially capable of revealing the natural history of the condition, and suggest that it may also be applicable generally as a specific targeting agent for diagnostic and even therapeutic purposes in clinical amyloidosis.

Concentration of Serum Amyloid P Component in the CSF as a Possible Marker of Cerebral Amyloid Deposits in Alzheimer′s Disease

1994 ◽  
Vol 201 (2) ◽  
pp. 722-726 ◽  
Author(s):  
P.N. Hawkins ◽  
M.N. Rossor ◽  
J.R. Gallimore ◽  
B. Miller ◽  
E.G. Moore ◽  
...  
Keyword(s):  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Cerebral Amyloid ◽  
Amyloid P

scholarly journals Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Nature ◽  
2010 ◽  
Vol 468 (7320) ◽  
pp. 93-97 ◽  
Author(s):  
Karl Bodin ◽  
Stephan Ellmerich ◽  
Melvyn C. Kahan ◽  
Glenys A. Tennent ◽  
Andrzej Loesch ◽  
...  
Keyword(s):  
Human Serum ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Serum Amyloid P-Component: Binding to Amyloid Fibrils and Immunohistochemical Staining in Normal Human Tissues

1980 ◽  
Vol 58 (2) ◽  
pp. 17P-18P
Author(s):  
M. B. Pepys ◽  
R. F. Dyck ◽  
F. C. de Beer ◽  
M. Kershaw
Keyword(s):  
Immunohistochemical Staining ◽  
Amyloid Fibrils ◽  
Serum Amyloid ◽  
Human Tissues ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Normal Human ◽  
Amyloid P

scholarly journals Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure.

1994 ◽  
Vol 91 (12) ◽  
pp. 5602-5606 ◽  
Author(s):  
M. B. Pepys ◽  
T. W. Rademacher ◽  
S. Amatayakul-Chantler ◽  
P. Williams ◽  
G. E. Noble ◽  
...  
Keyword(s):  
Human Serum ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

Is Serum Amyloid P Component Required for in Vivo Amyloid Deposition?

1996 ◽  
Vol 90 (s34) ◽  
pp. 33P-33P
Author(s):  
W L Hutchinson ◽  
J Herbert ◽  
P N Hawkins ◽  
M B Pepys
Keyword(s):  
Amyloid Deposition ◽  
Serum Amyloid ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid P
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