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

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Citation

Brinkmalm G, Portelius E, Ohrfelt A, Mattsson N, Persson R, Gustavsson MK, Vite CH, Gobom J, Mansson JE, Nilsson J, Halim A, Larson G, Ruetschi U, Zetterberg H, Blennow K, Brinkmalm A

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

J Mass Spectrom. 2012 May;47(5):591-603. doi: 10.1002/jms.2987.

PubMed ID
22576872 [ View in PubMed
]
Abstract

Amyloid precursor protein (APP) is the precursor protein to amyloid beta (Abeta), the main constituent of senile plaques in Alzheimer's disease (AD). Endogenous Abeta 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 Abeta 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/Abeta peptide species, thus enabling a deeper characterization of possible variants and PTMs. Abnormal APP/Abeta 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 Abeta was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human Abeta (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/Abeta peptide species in CSF by using an online top-down MS-based method.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Amyloid beta A4 proteinP05067Details