Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease.
Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer's disease (AD) Abeta peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger-Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger-Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Abeta immunoreactivity and morphological signs of degeneration as well as extracellular pE-Abeta deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Abeta formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Abeta formation.
Morawski
Markus
M
University of Leipzig, Leipzig, Germany.
Hartlage-Rübsamen
Maike
M
Jäger
Carsten
C
Waniek
Alexander
A
Schilling
Stephan
S
Schwab
Claudia
C
McGeer
Patrick L
PL
Arendt
Thomas
T
Demuth
Hans-Ulrich
HU
Rossner
Steffen
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D019881:Aminoacyltransferases / Q000172:deficiency / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000201:enzymology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008125:Locus Coeruleus / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008875:Middle Aged; D010487:Periaqueductal Gray / Q000201:enzymology*; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D054832:Urocortins / Q000378:metabolism
D016229:Amyloid beta-Peptides; C549377:Ucn1 protein, mouse; D054832:Urocortins; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid
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