Journal Mobile Options
Table of Contents
Vol. 6, No. 3, 2009
Issue release date: May 2009
Neurodegenerative Dis 2009;6:87–94

Identification of Novel APP/Aβ Isoforms in Human Cerebrospinal Fluid

Portelius E. · Brinkmalm G. · Tran A.J. · Zetterberg H. · Westman-Brinkmalm A. · Blennow K.
Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Aggregation of β-amyloid (Aβ) into oligomers and plaques is the central pathogenic mechanism in Alzheimer’s disease (AD). Aβ is produced from the amyloid precursor protein (APP) by β- and γ-secretases, whereas, in the nonamyloidogenic pathway, α-secretase cleaves within the Aβ sequence, and thus precludes Aβ formation. A lot of research has focused on Aβ production and the neurotoxic 42-amino-acid form of Aβ (Aβ1–42), while less is known about the nonamyloidogenic pathway and how Aβ is degraded. Objective: To study the Aβ metabolism in man by searching for novel Aβ peptides in cerebrospinal fluid (CSF). Methods: Immunoprecipitation, using an anti-Aβ antibody, 6E10, was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. Results: We identified 12 truncated APP/Aβ peptides in the CSF, all of which end at amino acid 15 in the Aβ sequence, i.e. 1 amino acid before the proposed α-secretase site. Of these 12 APP/Aβ peptides, 11 are novel peptides and start N-terminally of the β-secretase site. The most abundant APP/Aβ peptide starts 25 amino acids before the β-secretase site, APP/Aβ (–25 to 15), and had a concentration of approximately 80 pg/ml. The identity of all the APP/Aβ peptides was verified in a cohort of AD patients and controls. A first pilot study also showed that the intensity of several APP/Aβ peaks in CSF was higher in AD cases than in controls. Conclusion: These data suggest an enzymatic activity that cleaves the precursor protein in a specific manner that may reflect a novel metabolic pathway for APP and Aβ.

Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.


  1. Blennow K, de Leon MJ, Zetterberg H: Alzheimer’s disease. Lancet 2006;368:387–403.
  2. Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–890.
  3. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985;82:4245–4249.
  4. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733–736.
  5. Selkoe DJ: Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 2004;6:1054–1061.
  6. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ: Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990;248:1122–1124.
  7. Gowing E, Roher AE, Woods AS, Cotter RJ, Chaney M, Little SP, Ball MJ: Chemical characterization of a beta 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J Biol Chem 1994;269:10987–10990.
  8. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  9. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, et al: Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322–325.
  10. Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ: Beta-amyloid peptide and a 3-kda fragment are derived by distinct cellular mechanisms. J Biol Chem 1993;268:3021–3024.
  11. Portelius E, Zetterberg H, Andreasson U, Brinkmalm G, Andreasen N, Wallin A, Westman-Brinkmalm A, Blennow K: An Alzheimer’s disease-specific beta-amyloid fragment signature in cerebrospinal fluid. Neurosci Lett 2006;409:215–219.
  12. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (asp 2) as beta-secretase. Mol Cell Neurosci 1999;14:419–427.
  13. Sinha S, Lieberburg I: Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci USA 1999;96:11049–11053.
  14. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735–741.
  15. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999;402:533–537.
  16. Backstrom JR, Lim GP, Cullen MJ, Tokes ZA: Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1–40). J Neurosci 1996;16:7910–7919.
  17. Eckman EA, Reed DK, Eckman CB: Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem 2001;276:24540–24548.
  18. Roher AE, Kasunic TC, Woods AS, Cotter RJ, Ball MJ, Fridman R: Proteolysis of a beta peptide from Alzheimer disease brain by gelatinase A. Biochem Biophys Res Commun 1994;205:1755–1761.
  19. Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, Walker D, Scheff S, McGillis JP, Rydel RE, Estus S: The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci 2000;20:3937–3946.
  20. Andreasson U, Portelius E, Andersson ME, Blennow K, Zetterberg H: Aspects of β-amyloid as a biomarker for Alzheimer’s disease. Biomark Med 2007;1:59–78.
  21. Portelius E, Westman-Brinkmalm A, Zetterberg H, Blennow K: Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. J Proteome Res 2006;5:1010–1016.
  22. Portelius E, Tran A, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A: Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 2007;6:4433–4439.
  23. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L: Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234.
  24. Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL: Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 1990;248:492–495.
  25. Bradbury LE, LeBlanc JF, McCarthy DB: ProteinChip array-based amyloid beta assays. Methods Mol Biol 2004;264:245–257.
  26. Maruyama K, Kametani F, Usami M, Yamao-Harigaya W, Tanaka K: ‘Secretase,’ Alzheimer amyloid protein precursor secreting enzyme is not sequence-specific. Biochem Biophys Res Commun 1991;179:1670–1676.
  27. Sisodia SS: Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA 1992;89:6075–6079.
  28. Simons M, de Strooper B, Multhaup G, Tienari PJ, Dotti CG, Beyreuther K: Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J Neurosci 1996;16:899–908.
  29. Roepstorff P, Fohlman J: Proposal for a common nomenclature for sequence ions in mass spectra of peptides. Biomed Mass Spectrom 1984;11:601.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50