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Open Access 01-04-2015 | Original Paper

Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease

Authors: Maike Hartlage-Rübsamen, Alexander Waniek, Juliane Meißner, Markus Morawski, Stephan Schilling, Carsten Jäger, Martin Kleinschmidt, Holger Cynis, Astrid Kehlen, Thomas Arendt, Hans-Ulrich Demuth, Steffen Roßner

Published in: Acta Neuropathologica | Issue 4/2015

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.

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Title: Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease
Authors: Maike Hartlage-Rübsamen
Alexander Waniek
Juliane Meißner
Markus Morawski
Stephan Schilling
Carsten Jäger
Martin Kleinschmidt
Holger Cynis
Astrid Kehlen
Thomas Arendt
Hans-Ulrich Demuth
Steffen Roßner
Publication date: 01-04-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1395-2

At a glance: The STEP trials

Springer Medicine

Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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