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An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid β and amyloid precursor protein in human and cat cerebrospinal fluid.

Journal article
Authors Gunnar Brinkmalm
Erik Portelius
Annika Öhrfelt
Niklas Mattsson
Rita Persson
Mikael K Gustavsson
Charles H Vite
Johan Gobom
Jan-Eric Månsson
Jonas Nilsson
Adnan Halim
Göran Larson
Ulla Rüetschi
Henrik Zetterberg
Kaj Blennow
Ann Brinkmalm-Westman
Published in Journal of mass spectrometry : JMS
Volume 47
Issue 5
Pages 591-603
ISSN 1096-9888
Publication year 2012
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 591-603
Language en
Keywords Amino Acid Sequence, Amino Acid Substitution, Amyloid beta-Peptides, cerebrospinal fluid, chemistry, Amyloid beta-Protein Precursor, cerebrospinal fluid, chemistry, Animals, Cats, Chromatography, Liquid, methods, Glycosylation, Humans, Immunoprecipitation, Molecular Sequence Data, Sequence Alignment, Sequence Analysis, Protein, methods, Spectrometry, Mass, Electrospray Ionization, methods
Subject categories Neurology


Amyloid precursor protein (APP) is the precursor protein to amyloid β (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD). Endogenous Aβ peptides reflect the APP processing, and greater knowledge of different APP degradation pathways is important to understand the mechanism underlying AD pathology. When one analyzes longer Aβ peptides by low-energy collision-induced dissociation tandem mass spectrometry (MS/MS), mainly long b-fragments are observed, limiting the possibility to determine variations such as amino acid variants or post-translational modifications (PTMs) within the N-terminal half of the peptide. However, by using electron capture dissociation (ECD), we obtained a more comprehensive sequence coverage for several APP/Aβ peptide species, thus enabling a deeper characterization of possible variants and PTMs. Abnormal APP/Aβ processing has also been described in the lysosomal storage disease Niemann-Pick type C and the major large animal used for studying this disease is cat. By ECD MS/MS, a substitution of Asp7 → Glu in cat Aβ was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human Aβ (a previously unknown glycosylation type), were identified also in cat cerebrospinal fluid (CSF). It is therefore likely that this unusual type of glycosylation is common for (at least) species belonging to the magnorder Boreoeutheria. We here describe a detailed characterization of endogenous APP/Aβ peptide species in CSF by using an online top-down MS-based method.

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