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Vol. 6, No. 3, 2009
Issue release date: May 2009
Section title: Original Paper
Neurodegenerative Dis 2009;6:87–94
(DOI:10.1159/000203774)

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

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 6/17/2008
Accepted: 10/15/2008
Published online: 2/20/2009

Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 1

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD

Abstract

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.


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 6/17/2008
Accepted: 10/15/2008
Published online: 2/20/2009

Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 1

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


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