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Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis

Nature Medicine volume 6, pages 643–651 (2000)Cite this article

Abstract

Accumulation of fibrils composed of amyloid A in tissues resulting in displacement of normal structures and cellular dysfunction is the characteristic feature of systemic amyloidoses. Here we show that RAGE, a multiligand immunoglobulin superfamily cell surface molecule, is a receptor for the amyloidogenic form of serum amyloid A. Interactions between RAGE and amyloid A induced cellular perturbation. In a mouse model, amyloid A accumulation, evidence of cell stress and expression of RAGE were closely linked. Antagonizing RAGE suppressed cell stress and amyloid deposition in mouse spleens. These data indicate that RAGE is a potential target for inhibiting accumulation of amyloid A and for limiting cellular dysfunction induced by amyloid A.

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Figure 1: Expression of RAGE, deposition of amyloid A and expression of M-CSF in human spleen.
Figure 2: Interaction of RAGE with amyloid A fibrils, and RAGE-dependent activation of BV-2 transformed mononuclear phagocytes by SAA1.1.
Figure 3: Effect of RAGE blockade on systemic amyloidosis in a mouse model: plasma SAA levels, splenic NF-κB activation and expression of transcripts for cell stress markers.
Figure 4: Effect of RAGE blockade on systemic amyloidosis in a mouse model.
Figure 5: Soluble RAGE infusion in a mouse model of systemic amyloidosis: effect on splenic RAGE expression.
Figure 6: Effect of RAGE blockade in a mouse model of systemic amyloidosis: isolation of SAA–sRAGE complex from mouse plasma and effect on splenic amyloid deposition.
Figure 7: Amylin and prion-peptide-derived fibrils bind RAGE and mediate RAGE-dependent NF-kB actvation on BV-2 cells.

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Acknowledgements

This work was supported by grants from the US Public Health Service (AG00690, AG14103, AG12891, NS31220, HL56881 and HL69091), the Juvenile Diabetes Foundation International and the Surgical Research Fund.

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Authors and Affiliations

  1. Departments of Pathology, Physiology, and Surgery College of Physicians and Surgeons of Columbia University, New York, 10032, New York, USA

    Shi Du Yan, Huaijie Zhu, Aiping Zhu, Hong Du, Ann Marie Schmidt & David Stern

  2. New York State Institute for Basic Research, Staten Island, 10314, New York, USA

    Adam Golabek

  3. Haldeman Laboratory for Alzheimer's Disease Research, Sun Health Research Institute, Sun City, 85372, Arizona, USA

    Alex Roher

  4. Department of Biochemistry, Sanders-Brown Center on Aging, Stroke Program, University of Kentucky and Veterans Administration Medical Center, Lexington, 40506, Kentucky, USA

    Jin Yu & Mark Kindy

  5. Serono Pharmaceutical Research Institute, Geneva, Switzerland and University of Chile, Santiago, Chile

    Claudio Soto

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Correspondence to Shi Du Yan or Mark Kindy.

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Yan, S., Zhu, H., Zhu, A. et al. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis . Nat Med 6, 643–651 (2000). https://doi.org/10.1038/76216

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