Concerted action of dipeptidyl peptidase IV and glutaminyl cyclase results in formation of pyroglutamate-modified amyloid peptides in vitro

Compelling evidence suggests a crucial role of amyloid beta peptides (Aβ(1-40/42)) in the etiology of Alzheimer's disease (AD). The N-terminal truncation of Aβ(1-40/42) and their modification, e.g. by glutaminyl cyclase (QC), is expected to enhance the amyloid toxicity. In this work, the MALDI-...

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Veröffentlicht in:Neurochemistry international 2018-02, Vol.113, p.112-119
Hauptverfasser: Antonyan, Alvard, Schlenzig, Dagmar, Schilling, Stephan, Naumann, Marcel, Sharoyan, Svetlana, Mardanyan, Sona, Demuth, Hans-Ulrich
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container_start_page 112
container_title Neurochemistry international
container_volume 113
creator Antonyan, Alvard
Schlenzig, Dagmar
Schilling, Stephan
Naumann, Marcel
Sharoyan, Svetlana
Mardanyan, Sona
Demuth, Hans-Ulrich
description Compelling evidence suggests a crucial role of amyloid beta peptides (Aβ(1-40/42)) in the etiology of Alzheimer's disease (AD). The N-terminal truncation of Aβ(1-40/42) and their modification, e.g. by glutaminyl cyclase (QC), is expected to enhance the amyloid toxicity. In this work, the MALDI-TOF mass spectrometry application proved N-terminal cleavage of Aβ(1-40/42) by purified dipeptidyl peptidase IV (DPPIV) in vitro observed earlier. The subsequent transformation of resulted Aβ(3-40/42) to pE-Aβ(3-40/42) in QC catalyzed glutamate cyclization was manifested. Hence, consecutive conversion of Aβ(1-40/42) by DPPIV and QC can be assumed as a potential mechanism of formation of non-degrading pyroglutamated pE-Aβ(3-40/42), which might accumulate and contribute to AD progression. The in vitro acceleration of Aβ(1-40) aggregation in the simultaneous presence of DPPIV and QC was shown also. •MALDI-TOF analysis proved N-terminal dipeptide cleavage from Aβ(1-40/42) by DPPIV.•Action of DPPIV is followed by QC catalyzed transformation to pE-Aβ(3-40/42) in vitro.•The aggregation of Aβ(1-40/42) is hindered by DPPIV and accelerated by QC in vitro.
doi_str_mv 10.1016/j.neuint.2017.12.001
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subjects Amino Acid Sequence
Aminoacyltransferases - metabolism
Amyloid beta peptides
Amyloid beta-Peptides - analysis
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Animals
Cattle
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl peptidase IV
Enzyme-substrate interactions
Glutaminyl cyclase
Humans
MALDI-TOF mass spectrometry
Peptide Fragments - analysis
Peptide Fragments - genetics
Peptide Fragments - metabolism
Protein Aggregates - drug effects
Protein Aggregates - physiology
Pyrrolidonecarboxylic Acid - pharmacology
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods
title Concerted action of dipeptidyl peptidase IV and glutaminyl cyclase results in formation of pyroglutamate-modified amyloid peptides in vitro
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