Identification of Novel APP/Aβ Isoforms in Human Cerebrospinal FluidPortelius 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
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
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.
© 2009 S. Karger AG, Basel
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: 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 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.