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Cited by 26Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsIntracerebral and Subarachnoid Hemorrhage Research

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

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Al-Shawi, Raya, Tennent, Glenys A., Millar, David J., Richard-Londt, Angela, Brandner, Sebastian, Werring, David J., Simons, J. Paul, Pepys, Mark B.·2016·Open Biology
DOI 10.1098/rsob.150202PMC PMC4772805
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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.

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  • The binding of SAP stabilizes amyloid fibrils and promotes their formation in the brain, thereby contributing to the pathogenesis of AD and cerebral amyloid angiopathy.

    “The binding of SAP stabilizes amyloid fibrils85 and promotes their formation in the brain86,87, thereby contributing to the pathogenesis of AD and cerebral amyloid angiopathy88,89.”

    From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [89]

    The Background says SAP promotes fibril formation in vitro and stabilizes fibrils, and that it is likely to contribute to the persistence of amyloid deposits in vivo. It also says the role of amyloid fibrils in AD pathogenesis, if any, is unknown, while identifying a direct disease-causing role for amyloid in CAA. The claim overstates this qualified account as an established contribution to the pathogenesis of both conditions. (LLM, conf=0.87)

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Research works printed but not linked: 39

  1. [1]Glenner GG, Wong CW 1984 Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131– 1135. (doi:10.1016/0006-291X(84)91209-9) 6236805 · DOI · Paper page
  2. [2]De Strooper B, König G 1999 Alzheimer's disease. A firm base for drug development. Nature 402, 471– 472. (doi:10.1038/44973) 10591201 · DOI
  3. [3]Brunkan AL, Goate AM 2005 Presenilin function and γ-secretase activity. J. Neurochem. 93, 769– 792. (doi:10.1111/j.1471-4159.2005.03099.x) 15857382 · DOI
  4. [4]Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y, Schmitt-Ulms G, Fraser PE, St George-Hyslop PH 2015 Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways. Mol. Cell. Neurosci. 66, 3– 11. (doi:10.1016/j.mcn.2015.02.016) 25748120 PMC4503820 · DOI
  5. [5]Schneider LS et al. 2014 Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J. Intern. Med. 275, 251– 283. (doi:10.1111/joim.12191) 24605808 PMC3956752 · DOI · Paper page
  6. [6]Pepys MB 2006 Amyloidosis. Annu. Rev. Med. 57, 223– 241. (doi:10.1146/annurev.med.57.121304.131243) 16409147 · DOI
  7. [7]Hind CRK, Collins PM, Caspi D, Baltz ML, Pepys MB 1984 Specific chemical dissociation of fibrillar and non-fibrillar components of amyloid deposits. Lancet ii, 376– 378. (doi:10.1016/S0140-6736(84)90544-0) 6147456 · DOI
  8. [8]Tennent GA, Lovat LB, Pepys MB 1995 Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer's disease and systemic amyloidosis. Proc. Natl Acad. Sci. USA 92, 4299– 4303. (doi:10.1073/pnas.92.10.4299) 7753801 PMC41931 · DOI · Paper page
  9. [9]Pepys MB et al. 2002 Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417, 254– 259. (doi:10.1038/417254a) 12015594 · DOI · Paper page
  10. [10]Pepys MB, Dyck RF, de Beer FC, Skinner M, Cohen AS 1979 Binding of serum amyloid P component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 38, 284– 293. 118839 PMC1537850
  11. [11]Rowe IF, Jensson O, Lewis PD, Candy J, Tennent GA, Pepys MB 1984 Immunohistochemical demonstration of amyloid P component in cerebro-vascular amyloidosis. Neuropathol. Appl. Neurobiol. 10, 53– 61. (doi:10.1111/j.1365-2990.1984.tb00340.x) 6377111 · DOI
  12. [12]Coria F, Castano E, Prelli F, Larrondo-Lillo M, van Duinen S, Shelanski ML, Frangione B 1988 Isolation and characterization of amyloid P component from Alzheimer's disease and other types of cerebral amyloidosis. Lab. Invest. 58, 454– 458. 2965774
  13. [13]Duong T, Pommier EC, Scheibel AB 1989 Immunodetection of the amyloid P component in Alzheimer's disease. Acta Neuropathol. 78, 429– 437. (doi:10.1007/BF00688180) 2551124 · DOI
  14. [15]Hamazaki H 1995 Amyloid P component promotes aggregation of Alzheimer's β-amyloid peptide. Biochem. Biophys. Res. Commun. 211, 349– 353. (doi:10.1006/bbrc.1995.1819) 7794242 · DOI · Paper page
  15. [17]Noursadeghi M, Bickerstaff MCM, Gallimore JR, Herbert J, Cohen J, Pepys MB 2000 Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen. Proc. Natl Acad. Sci. USA 97, 14 584– 14 589. (doi:10.1073/pnas.97.26.14584) PMC18962 11121061 · DOI
  16. [19]Urbányi Z, Lakics V, Erdó SL 1994 Serum amyloid P component-induced cell death in primary cultures of rat cerebral cortex. Eur. J. Pharmacol. 270, 375– 388. (doi:10.1016/0926-6917(94)90016-7) 7805789 · DOI
  17. [20]Duong T, Acton PJ, Johnson RA 1998 The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions. Brain Res. 813, 303– 312. (doi:10.1016/S0006-8993(98)00966-4) 9838173 · DOI
  18. [21]Pisalyaput K, Tenner AJ 2008 Complement component C1q inhibits β-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J. Neurochem. 104, 696– 707. (doi:10.1111/j.1471-4159.2007.05012.x) 17986223 · DOI
  19. [22]Du Clos TW, Mold C, Stump RF 1990 Identification of a polypeptide sequence that mediates nuclear localization of the acute phase protein C-reactive protein. J. Immunol. 145, 3869– 3875. 2246517
  20. [23]Pepys MB, Booth SE, Tennent GA, Butler PJG, Williams DG 1994 Binding of pentraxins to different nuclear structures: C-reactive protein binds to small nuclear ribonucleoprotein particles, serum amyloid P component binds to chromatin and nucleoli. Clin. Exp. Immunol. 97, 152– 157. (doi:10.1111/j.1365-2249.1994.tb06594.x) 8033412 PMC1534802 · DOI
  21. [25]Hawrylycz MJ et al. 2012 An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391– 399. (doi:10.1038/nature11405) 22996553 PMC4243026 · DOI · Paper page
  22. [26]Hawkins PN, Rossor MN, Gallimore JR, Miller B, Moore EG, Pepys MB 1994 Concentration of serum amyloid P component in the CSF as a possible marker of cerebral amyloid deposits in Alzheimer's disease. Biochem. Biophys. Res. Commun. 201, 722– 726. (doi:10.1006/bbrc.1994.1760) 7516157 · DOI
  23. [27]Nelson SR, Tennent GA, Sethi D, Gower PE, Ballardie FW, Amatayakul-Chantler S, Pepys MB 1991 Serum amyloid P component in chronic renal failure and dialysis. Clin. Chim. Acta 200, 191– 200. (doi:10.1016/0009-8981(91)90090-Y) 1777968 · DOI
  24. [28]Crawford JR, Bjorklund NL, Taglialatela G, Gomer RH 2012 Brain serum amyloid P levels are reduced in individuals that lack dementia while having Alzheimer's disease neuropathology. Neurochem. Res. 37, 795– 801. (doi:10.1007/s11064-011-0674-0) 22205573 PMC3299926 · DOI
  25. [29]Gillmore JD et al. 2010 Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br. J. Haematol. 148, 760– 767. (doi:10.1111/j.1365-2141.2009.08036.x) 20064157 · DOI
  26. [30]Kolstoe SE et al. 2009 Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component. Proc. Natl Acad. Sci. USA 106, 7619– 7623. (doi:10.1073/pnas.0902640106) 19372378 PMC2669789 · DOI
  27. [31]Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold K-H, Tolnay M, Staufenbiel M, Jucker M 2001 Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci. 21, 1619– 1627. 11222652 PMC6762950
  28. [33]Millar DJ, Hutchinson WL, Pepys MB 2011 Immunoradiometric assay for human serum amyloid P component. J. Immunol. Methods 371, 18– 24. (doi:10.1016/j.jim.2011.06.010) 21708157 · DOI
  29. [34]Puchtler H, Waldrop FS, Meloan SN 1985 A review of light, polarization and fluorescence microscopic methods for amyloid. Appl. Pathol. 3, 5– 17. 2429683
  30. [35]Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW, Greenberg SM, Bacskai BJ, Frosch MP 2005 Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J. Neuropathol. Exp. Neurol. 64, 588– 594. (doi:10.1097/01.jnen.0000171644.00180.fc) 16042310 · DOI
  31. [36]Breathnach SM, Melrose SM, Bhogal B, de Beer FC, Dyck RF, Tennent G, Black MM, Pepys MB 1981 Amyloid P component is located on elastic fibre microfibrils of normal human tissues. Nature 293, 652– 654. (doi:10.1038/293652a0) 7290201 · DOI
  32. [37]Westermark P, Shirahama T, Skinner M, Brun A, Cameron R, Cohen AS 1982 Immunohistochemical evidence for the lack of amyloid P component in some intracerebral amyloids. Lab. Invest. 46, 457– 460. 7043084
  33. [39]Gregoire SM et al. 2011 Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study. Brain 134, 2376– 2386. (doi:10.1093/brain/awr172) 21841203 · DOI
  34. [40]Gurol ME et al. 2012 Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology 79, 320– 326. (doi:10.1212/WNL.0b013e31826043a9) 22786597 PMC3400097 · DOI
  35. [41]Dumas A et al. 2012 Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy. Ann. Neurol. 72, 76– 81. (doi:10.1002/ana.23566) 22829269 PMC3408630 · DOI
  36. [42]Peca S et al. 2013 Neurovascular decoupling is associated with severity of cerebral amyloid angiopathy. Neurology 81, 1659– 1665. (doi:10.1212/01.wnl.0000435291.49598.54) 24097810 PMC3812103 · DOI
  37. [43]Pendlebury ST, Rothwell PM 2009 Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 8, 1006– 1018. (doi:10.1016/s1474-4422(09)70236-4) 19782001 · DOI · Paper page
  38. [44]Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA, Schneider JA 2011 Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann. Neurol. 69, 320– 327. (doi:10.1002/ana.22112) 21387377 PMC3228518 · DOI · Paper page
  39. [45]Poels MMF, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP, Breteler MMB, Vernooij MW 2012 Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology 78, 326– 333. (doi:10.1212/WNL.0b013e3182452928) 22262748 · DOI · Paper page

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Authors
Al-Shawi, R., Tennent, G. A., Millar, D. J., Richard-Londt, A., Brandner, S., Werring, D. J., Simons, J. P., & Pepys, M. B.
Affiliations
  • Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK
  • The Royal Free Hospital (GB)
  • Division of Neuropathology and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
  • UCL Queen Square Institute of Neurology (GB)
Corresponding author
Pepys, Mark B.
ORCID
Venue
Open Biology
Publisher
The Royal Society
Published
2016-02
Volume
6
Issue
2
Pages
150202
ISSN
2046-2441 (ISSN-L)
DOI
10.1098/rsob.150202
PMC
PMC4772805
OpenAlex
W2266491555
Cited by
26
References
6
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 2
FWCI
2.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Open Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wolfson Foundation (NA)
  • UCL Amyloidosis Research Fund (NA)
  • UK NIHR BRC core support (NA)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
serum amyloid P component, amyloid-beta, Alzheimer's disease, cerebral amyloid angiopathy, transgenic mouse model, cerebrospinal fluid, amyloid fibril formation
MeSH terms
Alzheimer Disease, Serum Amyloid P-Component, Animals, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Transgenic, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Mice, Plaque, Amyloid, Protein Aggregation, Pathological

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