Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins are deposited as insoluble fibrils that disrupt tissue structure. Over 20 unrelated proteins form amyloid in vivo, with fibrils sharing a cross-β-sheet structure composed of non-covalently associated protein or peptide subunits. Glycosaminoglycans and serum amyloid P component are universal non-fibrillar constituents of amyloid, contributing to fibrillogenesis and the stability of amyloid deposits. Amyloidosis may be acquired or hereditary and local or systemic, and is classified according to the precursor protein. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins, reversion of misfolded proteins to their native state, inhibition of fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component.

Keywords:
Amyloid, Amyloidosis, Pharmacological strategies, Serum amyloid P component
1.
Pepys MB: Amyloidosis; in Weatherall DJ, Ledingham JGG, Warrell DA (eds): Oxford Textbook of Medicine, ed 3. Oxford, Oxford University Press, 1996, pp 1512–1524.
2.
Dobson CM, Ellis RJ, Fersht AR (eds): Protein Misfolding and Disease. London, The Royal Society, 2001.
3.
Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN: Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24–29.
4.
Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD et al: Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346:1786–1791.
5.
Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, Fraser PE et al: Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 1997;385:787–793.
6.
Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG, Szarek WA: Arresting amyloidosis in vivo using small molecule anionic sulphonates or sulphates: Implications for Alzheimer’s disease. Nat Med 1995;1:143–148.
7.
Klabunde T, Petrassi HM, Oza VB, Raman P, Kelly JW, Sacchettini JC: Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol 2000;7:312–321.
8.
Soto C: Plaque busters: Strategies to inhibit amyloid formation in Alzheimer’s disease. Mol Med Today 1999;5:343–350.
9.
Kisilevsky R, Szarek WA: Novel glycosaminoglycan precursors as anti-amyloid agents. II. J Mol Neurosci 2002;19:45–50.
10.
Sigurdsson EM, Permanne B, Soto C et al: In vivo reversal of amyloid-β lesions in rat brain. J Neuropathol Exp Neurol 2000;59:11–17.
11.
O’Nuallain B, Wetzel R: Conformational Abs recognizing a generic amyloid fibril epitope. Proc Natl Acad Sci USA 2002;99:1485–1490.
12.
Hrncic R, Wall J, Wolfenbarger DA, Murphy CL, Schell M, Weiss DT et al: Antibody-mediated resolution of light chain-associated amyloid deposits. Am J Pathol 2000;157:1239–1246.
13.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H et al: Peripherally administered antibodies against amyloid 1-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916–919.
14.
Bishop GM, Robinson SR, Smith MA, Perry G, Atwood CS: Call for Elan to publish Alzheimer’s trial details (letter). Nature 2002;416:667.
15.
Tennent GA, Lovat LB, Pepys MB: Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer’s disease and systemic amyloidosis. Proc Natl Acad Sci USA 1995;92:4299–4303.
16.
Botto M, Hawkins PN, Bickerstaff MCM, Herbert J, Bygrave AE, McBride A et al: Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nat Med 1997;3:855–859.
17.
Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR et al: Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002;417:254–259.
© 2003 S. Karger AG, Basel
2004
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.