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

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.

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Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Nature ◽

10.1038/nature09494 ◽

2010 ◽

Vol 468 (7320) ◽

pp. 93-97 ◽

Cited By ~ 215

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

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.12.5602 ◽

1994 ◽

Vol 91 (12) ◽

pp. 5602-5606 ◽

Cited By ~ 138

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

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

Journal of Experimental Medicine ◽

10.1084/jem.159.4.1058 ◽

1984 ◽

Vol 159 (4) ◽

pp. 1058-1069 ◽

Cited By ~ 96

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.

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Amyloidosis

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0241 ◽

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).

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Immunotherapeutic clearance of systemic amyloid deposits by antibodies to serum amyloid P component

Amyloid ◽

10.1080/13506129.2016.1269735 ◽

2016 ◽

Vol 24 (sup1) ◽

pp. 5-6 ◽

Cited By ~ 1

Author(s):

Mark B. Pepys

Keyword(s):

Serum Amyloid ◽

Amyloid P Component ◽

Serum Amyloid P ◽

Serum Amyloid P Component ◽

Amyloid Deposits ◽

Amyloid P

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Faculty Opinions recommendation of Antibodies to human serum amyloid P component eliminate visceral amyloid deposits.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.6761956.9295059 ◽

2011 ◽

Author(s):

Richard Gomer

Keyword(s):

Human Serum ◽

Serum Amyloid ◽

Amyloid P Component ◽

Serum Amyloid P ◽

Serum Amyloid P Component ◽

Amyloid Deposits ◽

Amyloid P

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Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis

Science Translational Medicine ◽

10.1126/scitranslmed.aan3128 ◽

2018 ◽

Vol 10 (422) ◽

pp. eaan3128 ◽

Cited By ~ 47

Author(s):

Duncan B. Richards ◽

Louise M. Cookson ◽

Sharon V. Barton ◽

Lia Liefaard ◽

Thirusha Lane ◽

...

Keyword(s):

Extracellular Volume ◽

Serum Amyloid ◽

Systemic Amyloidosis ◽

Whole Body ◽

Amyloid P Component ◽

Serum Amyloid P ◽

Serum Amyloid P Component ◽

Amyloid Deposits ◽

Amyloid Load ◽

Amyloid P

Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier:NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of123I-labeled SAP or of99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests.123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.

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

Open Biology ◽

10.1098/rsob.150202 ◽

2016 ◽

Vol 6 (2) ◽

pp. 150202 ◽

Cited By ~ 11

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.

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