Pharmacological Removal of Serum Amyloid P Component from Intracerebral Plaques and Cerebrovascular Aβ Amyloid Deposits in Vivo

Overview

Journal Open Biol

Specialties Biology
Cell Biology
Molecular Biology

Date 2016 Feb 5

PMID 26842068

Citations 12

Authors

Raya Al-Shawi

Glenys A Tennent

David J Millar

Angela Richard-Londt

Sebastian Brandner

David J Werring

J Paul Simons

Mark B Pepys

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders.

Schmidt A, Finan C, Chopade S, Ellmerich S, Rossor M, Hingorani A Open Biol. 2024; 14(7):230419.

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Serum amyloid P component accumulates and persists in neurones following traumatic brain injury.

Yip P, Liu Z, Hasan S, Pepys M, Uff C Open Biol. 2023; 13(12):230253.

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Dementia in the older population is associated with neocortex content of serum amyloid P component.

Ellmerich S, Taylor G, Richardson C, Minett T, Schmidt A, Brayne C Brain Commun. 2021; 3(4):fcab225.

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References

Duong T, Acton P, Johnson R . The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions. Brain Res. 1998; 813(2):303-12. DOI: 10.1016/s0006-8993(98)00966-4. View

Botto M, Hawkins P, Bickerstaff M, Herbert J, Bygrave A, McBride A . Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nat Med. 1997; 3(8):855-9. DOI: 10.1038/nm0897-855. View

Domnitz S, Robbins E, Hoang A, Garcia-Alloza M, Hyman B, Rebeck G . Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol. 2005; 64(7):588-94. DOI: 10.1097/01.jnen.0000171644.00180.fc. View

Millar D, Hutchinson W, Pepys M . Immunoradiometric assay for human serum amyloid P component. J Immunol Methods. 2011; 371(1-2):18-24. DOI: 10.1016/j.jim.2011.06.010. View

Gregoire S, Charidimou A, Gadapa N, Dolan E, Antoun N, Peeters A . Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study. Brain. 2011; 134(Pt 8):2376-86. DOI: 10.1093/brain/awr172. View

Charidimou A, Gang Q, Werring D . Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry. 2011; 83(2):124-37. DOI: 10.1136/jnnp-2011-301308. View

Poels M, Ikram M, van der Lugt A, Hofman A, Niessen W, Krestin G . Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012; 78(5):326-33. DOI: 10.1212/WNL.0b013e3182452928. View

Crawford J, Bjorklund N, Taglialatela G, Gomer R . Brain serum amyloid P levels are reduced in individuals that lack dementia while having Alzheimer's disease neuropathology. Neurochem Res. 2011; 37(4):795-801. PMC: 3299926. DOI: 10.1007/s11064-011-0674-0. View

Mold M, Shrive A, Exley C . Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of amyloid-β42. J Alzheimers Dis. 2012; 29(4):875-81. DOI: 10.3233/JAD-2012-120076. View

10.

Gurol M, Dierksen G, Betensky R, Gidicsin C, Halpin A, Becker A . Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology. 2012; 79(4):320-6. PMC: 3400097. DOI: 10.1212/WNL.0b013e31826043a9. View

11.

Dumas A, Dierksen G, Gurol M, Halpin A, Martinez-Ramirez S, Schwab K . Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy. Ann Neurol. 2012; 72(1):76-81. PMC: 3408630. DOI: 10.1002/ana.23566. View

12.

Hawrylycz M, Lein E, Guillozet-Bongaarts A, Shen E, Ng L, Miller J . An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012; 489(7416):391-399. PMC: 4243026. DOI: 10.1038/nature11405. View

13.

Peca S, McCreary C, Donaldson E, Kumarpillai G, Shobha N, Sanchez K . Neurovascular decoupling is associated with severity of cerebral amyloid angiopathy. Neurology. 2013; 81(19):1659-65. PMC: 3812103. DOI: 10.1212/01.wnl.0000435291.49598.54. View

14.

Hong Y, Veenith T, Dewar D, Outtrim J, Mani V, Williams C . Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol. 2013; 71(1):23-31. PMC: 4084932. DOI: 10.1001/jamaneurol.2013.4847. View

15.

Schneider L, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R . Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. 2014; 275(3):251-83. PMC: 3956752. DOI: 10.1111/joim.12191. View

16.

Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y . Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways. Mol Cell Neurosci. 2015; 66(Pt A):3-11. PMC: 4503820. DOI: 10.1016/j.mcn.2015.02.016. View

17.

Pepys M . Amyloidosis. Annu Rev Med. 2006; 57:223-41. DOI: 10.1146/annurev.med.57.121304.131243. View

18.

Pisalyaput K, Tenner A . Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 2007; 104(3):696-707. DOI: 10.1111/j.1471-4159.2007.05012.x. View

19.

Kolstoe S, Ridha B, Bellotti V, Wang N, Robinson C, Crutch S . Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component. Proc Natl Acad Sci U S A. 2009; 106(18):7619-23. PMC: 2669789. DOI: 10.1073/pnas.0902640106. View

20.

Pendlebury S, Rothwell P . Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 2009; 8(11):1006-18. DOI: 10.1016/S1474-4422(09)70236-4. View