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

• DOI: 10.1007/s00401-015-1395-2
• Publication Date: 2015-02-10T05:29:48Z
• Authors: Maike Hartlage-Rü...; Alexander Waniek; Juliane Meißner; Markus Morawski; Stephan Schilling; Carsten Jäger; Martin Kleinschmidt; Holger Cynis; Astrid Kehlen; Thomas Arendt; Hans-Ulrich Demuth; Steffen Roßner
• Keywords: Male; Clinical Neurology; Mice, Transgenic; Pathology and Forensic Medicine; Cellular and Molecular Neuroscience; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Alzheimer Disease; Glial Fibrillary Acidic Protein; Animals; Humans; Cells, Cultured; Chemokine CCL2; Aged; Aged, 80 and over; Original Paper; 0303 health sciences; Amyloid beta-Peptides; Age Factors; Brain; Aminoacyltransferases; Mice, Inbred C57BL; Disease Models, Animal; Astrocytes; Female

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.