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Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid {beta}-peptides in human cerebrospinal fluid.

Journal article
Authors Adnan Halim
Gunnar Brinkmalm
Ulla Rüetschi
Ann Brinkmalm-Westman
Erik Portelius
Henrik Zetterberg
Kaj Blennow
Göran Larson
Jonas Nilsson
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 108
Issue 29
Pages 11848-53
ISSN 1091-6490
Publication year 2011
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 11848-53
Language en
Links dx.doi.org/10.1073/pnas.1102664108
Subject categories Neurochemistry, Clinical chemistry, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Abstract

The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid β (Aβ)-peptides, e.g., Aβ1-42, is considered a critical step in the pathogenesis of Alzheimer's disease (AD). Although APP is a well-known membrane glycoprotein carrying both N- and O-glycans, nothing is known about the occurrence of released APP/Aβ glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified Aβ peptides and glycopeptides from CSF samples and then liquid chromatography-tandem mass spectrometry for structural analysis using collision-induced dissociation and electron capture dissociation. In addition to 33 unglycosylated APP/Aβ peptides, we identified 37 APP/Aβ glycopeptides with sialylated core 1 like O-glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/AβX-15 glycopeptides, where X was -63, -57, -52, and -45, in relation to Asp1 of the Aβ sequence. Unexpectedly, we also identified a series of 27 glycopeptides, the Aβ1-X series, where X was 20 (DAEFRHDSGYEVHHQKLVFF), 19, 18, 17, 16, and 15, which were all uniquely glycosylated on Tyr10. The Tyr10 linked O-glycans were (Neu5Ac)(1-2)Hex(Neu5Ac)HexNAc-O- structures with the disialylated terminals occasionally O-acetylated or lactonized, indicating a terminal Neu5Acα2,8Neu5Ac linkage. We could not detect any glycosylation of the Aβ1-38/40/42 isoforms. We observed an increase of up to 2.5 times of Tyr10 glycosylated Aβ peptides in CSF in six AD patients compared to seven non-AD patients. APP/Aβ sialylated O-glycans, including that of a Tyr residue, the first in a mammalian protein, may modulate APP processing, inhibiting the amyloidogenic pathway associated with AD.

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