Inhibition of glutaminyl cyclase prevents pGlu-Abeta formation after intracortical/hippocampal microinjection in vivo/in situ.
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.
Schilling
Stephan
S
Probiodrug AG, Halle (Saale), Germany.
Appl
Thomas
T
Hoffmann
Torsten
T
Cynis
Holger
H
Schulz
Katrin
K
Jagla
Wolfgang
W
Friedrich
Daniel
D
Wermann
Michael
M
Buchholz
Mirko
M
Heiser
Ulrich
U
von Hörsten
Stephan
S
Demuth
Hans-Ulrich
HU
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
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid