title: Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer's disease.
abstract: The brains of Alzheimer's disease (AD) patients are characterized by deposits of Abeta peptides and by accompanying chronic inflammation. Here, we provide evidence that the enzyme isoglutaminyl cyclase (isoQC) is a novel factor contributing to both aspects of AD pathology. Two putative substrates of isoQC, N-truncated Abeta peptides and the monocyte chemoattractant chemokine CCL2, undergo isoQC-catalyzed pyroglutamate (pGlu) modification. This triggers Abeta aggregation and facilitates the biological activity of CCL2, which collectively results in the formation of high molecular weight Abeta aggregates, glial cell activation, neuroinflammation and neuronal cell death. In mouse brain, we found isoQC to be neuron-specifically expressed in neocortical, hippocampal and subcortical structures, localized to the endoplasmic reticulum and Golgi apparatus as well as co-expressed with its substrate CCL2. In aged APP transgenic Tg2576 mice, both isoQC and CCL2 mRNA levels are up-regulated and isoQC and CCL2 proteins were found to be co-induced in Abeta plaque-associated reactive astrocytes. Also, in mouse primary astrocyte culture, a simultaneous up-regulation of isoQC and CCL2 expression was revealed upon Abeta and pGlu-Abeta stimulation. In brains of AD patients, the expression of isoQC and CCL2 mRNA and protein is up-regulated compared to controls and correlates with pGlu-Abeta load and with the decline in mini-mental state examination. Our observations provide evidence for a dual involvement of isoQC in AD pathogenesis by catalysis of pGlu-Abeta and pGlu-CCL2 formation which mutually stimulate inflammatory events and affect cognition. We conclude that isoQC inhibition may target both major pathological events in the development of AD.
authors: Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109, Leipzig, Germany.
authors: Maike
authors: M
authors: Hartlage-Rübsamen
authors: Alexander
authors: A
authors: Waniek
authors: Juliane
authors: J
authors: Meissner
authors: Markus
authors: M
authors: Morawski
authors: Stephan
authors: S
authors: Schilling
authors: Carsten
authors: C
authors: Jäger
authors: Martin
authors: M
authors: Kleinschmidt
authors: Holger
authors: H
authors: Cynis
authors: Astrid
authors: A
authors: Kehlen
authors: Thomas
authors: T
authors: Arendt
authors: Hans-Ulrich
authors: HU
authors: Demuth
authors: Steffen
authors: S
authors: Rossner
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase