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


ABSTRACT: The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid ? (A?)-peptides, e.g., A?1-42, 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/A? glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified A? 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/A? peptides, we identified 37 APP/A? glycopeptides with sialylated core 1 like O-glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/A?X-15 glycopeptides, where X was -63, -57, -52, and -45, in relation to Asp1 of the A? sequence. Unexpectedly, we also identified a series of 27 glycopeptides, the A?1-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 Neu5Ac?2,8Neu5Ac linkage. We could not detect any glycosylation of the A?1-38/40/42 isoforms. We observed an increase of up to 2.5 times of Tyr10 glycosylated A? peptides in CSF in six AD patients compared to seven non-AD patients. APP/A? 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.

SUBMITTER: Halim A 

PROVIDER: S-EPMC3141957 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Halim Adnan A   Brinkmalm Gunnar G   Brinkmalm Gunnar G   Rüetschi Ulla U   Westman-Brinkmalm Ann A   Portelius Erik E   Zetterberg Henrik H   Blennow Kaj K   Larson Göran G   Nilsson Jonas J  

Proceedings of the National Academy of Sciences of the United States of America 20110628 29


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 liqu  ...[more]

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