| Title |
Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease
|
|---|---|
| Published in |
Acta Neuropathologica, February 2015
|
| DOI | 10.1007/s00401-015-1395-2 |
| Pubmed ID | |
| 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 |
| 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. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 56 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Germany | 1 | 2% |
| Unknown | 55 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 9 | 16% |
| Student > Ph. D. Student | 7 | 13% |
| Researcher | 5 | 9% |
| Student > Bachelor | 5 | 9% |
| Student > Doctoral Student | 4 | 7% |
| Other | 8 | 14% |
| Unknown | 18 | 32% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 10 | 18% |
| Pharmacology, Toxicology and Pharmaceutical Science | 6 | 11% |
| Medicine and Dentistry | 5 | 9% |
| Agricultural and Biological Sciences | 5 | 9% |
| Biochemistry, Genetics and Molecular Biology | 4 | 7% |
| Other | 7 | 13% |
| Unknown | 19 | 34% |
Attention Score in Context
This research output has an Altmetric Attention Score of 25. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 August 2021.
All research outputs
#1,453,031
of 24,682,395 outputs
Outputs from Acta Neuropathologica
#257
of 2,508 outputs
Outputs of similar age
#20,963
of 367,968 outputs
Outputs of similar age from Acta Neuropathologica
#5
of 32 outputs
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