Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro

Ozawa, Daisaku; Nomura, Ryo; Mangione, Palma; Hara, Kazuhiro; Okoshi, Tadakazu; Porcari, Riccardo; Bellotti, Vittorio; Naiki, Hironobu

doi:10.1038/srep29077

Cited by 21 publications

(12 citation statements)

References 54 publications

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“…Interestingly, in our in vitro analysis, SAP appeared to delay fibril formation of I59T within the first hours of the aggregation process. A similar phenomenon was detected in vitro by Ozawa et al where SAP, in the presence of Ca 2+ , was found to first inhibit amyloid fibril formation of D76N β2-microglobulin (β2-m) and then accelerated D76N β2-m amyloid fibril formation [35]. The study showed that doughnut-shaped pentameric SAP coated the surface of the D76N β2-m fibrils.…”

Section: Sap Promotes the Formation Of Amyloid-like Lysozyme Aggregatsupporting

confidence: 80%

Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme

et al. 2020

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Many conflicting reports about the involvement of serum amyloid P component (SAP) in amyloid diseases have been presented over the years; SAP is known to be a universal component of amyloid aggregates but it has been suggested that it can both induce and suppress amyloid formation. By using our Drosophila model of systemic lysozyme amyloidosis, SAP has previously been shown to reduce the toxicity induced by the expression of the disease-associated lysozyme variant, F57I, in the Drosophila central nervous system. This study further investigates the involvement of SAP in modulating lysozyme toxicity using histochemistry and spectral analyses on the double transgenic WT and F57I lysozyme flies to probe; i) formation of aggregates, ii) morphological differences of the aggregated lysozyme species formed in the presence or absence of SAP, iii) location of lysozyme and iv) co-localisation of lysozyme and SAP in the fly brain. We found that SAP can counteract the toxicity (measured by the reduction in the median survival time) induced by F57I lysozyme by converting toxic F57I species into less toxic amyloid-like structures, as reflected by the spectral changes that p-FTAA undergoes when bound to lysozyme deposits in F57I-F57I-SAP flies as compared to F57I-F57I flies. Indeed, when SAP was introduced to in vitro lysozyme fibril formation, the endpoint fibrils had enhanced ThT fluorescence intensity as compared to lysozyme fibrils alone. This suggests that a general mechanism for SAP's role in amyloid diseases may be to promote the formation of stable, amyloid-like fibrils, thus decreasing the impact of toxic species formed along the aggregation pathway.

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Section: Sap Promotes the Formation Of Amyloid-like Lysozyme Aggregatsupporting

confidence: 80%

Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme

et al. 2020

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“…Agrawal et al ( 20 , 21 ) reported that in an in vitro acidic solution, npCRP was able to bind to various types of proteins with altered conformations in a calcium-independent manner. Taking into account acidic pH at inflammatory sites, npCRP protects against toxic conditions caused by protein misfolding and aggregation maintaining extracellular proteostasis of the inflammatory site by inhibiting the aggregation of unfolded/misfolded proteins ( 22 ). In addition, a dramatic increase in expression of mCRP has been observed in blood vessels of damaged brain regions.…”

Section: Role Of Crp In Inflammationmentioning

confidence: 99%

Monomeric C-Reactive Protein and Cerebral Hemorrhage: From Bench to Bedside

Napoli¹,

Slevin

Popa‐Wagner

et al. 2018

Front. Immunol.

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C-reactive protein (CRP) is an important mediator and a hallmark of the acute-phase response to inflammation. High-sensitivity assays that accurately measure levels of CRP have been recommended for use in risk assessment in ischemic stroke patients. Elevation of CRP during the acute-phase response in intracerebral hemorrhage (ICH) is also associated with the outcomes such as death and vascular complications. However, no association has been found with the increased risk of ICH. The aim of this review is to synthesize the published literature on the associations of CRP with acute ICH both as a risk biomarker and predictor of short- and long-term outcomes as well as its role as a pathogenic determinant. We believe before any clinical utility, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required both to evaluate the current state of knowledge and to improve the design of future clinical studies.

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“…Based on refolding studies using lactate dehydrogenase, SAP has been suggested to perform a chaperone-like role in reducing aggregation generally (Coker et al 2000 ). Recent findings point to Ca 2+ -dependent binding of the SAP pentamer to Aβ40 in both monomeric and fibril forms (Ozawa et al 2016 ), although the precise molecular details of these interactions are not known. Since SAP has the ability to bind both GAGs and amyloid fibrils, it is likely an important modulator of protein aggregation and plaque formation.…”

Section: Part 1: Carbohydratesmentioning

confidence: 99%

Amyloid plaques beyond Aβ: a survey of the diverse modulators of amyloid aggregation

Stewart

Radford

2017

Biophys Rev

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Aggregation of the amyloid-β (Aβ) peptide is strongly correlated with Alzheimer’s disease (AD). Recent research has improved our understanding of the kinetics of amyloid fibril assembly and revealed new details regarding different stages in plaque formation. Presently, interest is turning toward studying this process in a holistic context, focusing on cellular components which interact with the Aβ peptide at various junctures during aggregation, from monomer to cross-β amyloid fibrils. However, even in isolation, a multitude of factors including protein purity, pH, salt content, and agitation affect Aβ fibril formation and deposition, often producing complicated and conflicting results. The failure of numerous inhibitors in clinical trials for AD suggests that a detailed examination of the complex interactions that occur during plaque formation, including binding of carbohydrates, lipids, nucleic acids, and metal ions, is important for understanding the diversity of manifestations of the disease. Unraveling how a variety of key macromolecular modulators interact with the Aβ peptide and change its aggregation properties may provide opportunities for developing therapies. Since no protein acts in isolation, the interplay of these diverse molecules may differentiate disease onset, progression, and severity, and thus are worth careful consideration.

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Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro

Cited by 21 publications

References 54 publications

Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme

Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme

Monomeric C-Reactive Protein and Cerebral Hemorrhage: From Bench to Bedside

Amyloid plaques beyond Aβ: a survey of the diverse modulators of amyloid aggregation

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