title: Inhibition of glutaminyl cyclase prevents pGlu-Abeta formation after intracortical/hippocampal microinjection in vivo/in situ.
abstract: Modified amyloid beta (Abeta) peptides represent major constituents of the amyloid deposits in Alzheimer's disease and Down's syndrome. In particular, N-terminal pyroglutamate (pGlu) following truncation renders Abeta more stable, increases hydrophobicity and the aggregation velocity. Recent evidence based on in vitro studies suggests that the cyclization of glutamic acid, leading to pGlu-Abeta, is catalyzed by the enzyme glutaminyl cyclase (QC) following limited proteolysis of Abeta at the N-terminus. Here, we studied the pGlu-formation by rat QC in vitro as well as after microinjection of Abeta(1-40) and Abeta(3-40) into the rat cortex in vivo/in situ with and without pharmacological QC inhibition. Significant pGlu-Abeta formation was observed following injection of Abeta(3-40) after 24 h, indicating a catalyzed process. The generation of pGlu-Abeta from Abeta(3-40) was significantly inhibited by intracortical microinjection of a QC inhibitor. The study provides first evidence that generation of pGlu-Abeta is a QC-catalyzed process in vivo. The approach per se offers a strategy for a rapid evaluation of compounds targeting a reduction of pGlu formation at the N-terminus of amyloid peptides.
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Thomas
authors.initials: T
authors.lastname: Appl
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Katrin
authors.initials: K
authors.lastname: Schulz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jagla
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedrich
authors.forename: Michael
authors.initials: M
authors.lastname: Wermann
authors.forename: Mirko
authors.initials: M
authors.lastname: Buchholz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008845:Microinjections; D011761:Pyrrolidonecarboxylic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid