Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology.
Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.
Schilling
Stephan
S
Probiodrug AG, Weinbergweg 22, 06120 Halle/S., Germany.
Zeitschel
Ulrike
U
Hoffmann
Torsten
T
Heiser
Ulrich
U
Francke
Mike
M
Kehlen
Astrid
A
Holzer
Max
M
Hutter-Paier
Birgit
B
Prokesch
Manuela
M
Windisch
Manfred
M
Jagla
Wolfgang
W
Schlenzig
Dagmar
D
Lindner
Christiane
C
Rudolph
Thomas
T
Reuter
Gunter
G
Cynis
Holger
H
Montag
Dirk
D
Demuth
Hans-Ulrich
HU
Rossner
Steffen
S
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid