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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1395-2) contains supplementary material, which is available to authorized users.
Highlights
Amyloid pathology and neuroinflammation including activation of glial cells are key hallmarks of the neuropathology in brains of Alzheimer’s disease (AD) patients
The labeling generated by the isoQC antiserum 3285 in wild-type mouse brain was completely absent in isoQC knock-out but not in QC knock-out mouse brain tissue demonstrating the specificity of this antiserum for isoQC (Fig. 1b)
The conversion of Gln-CCL2 by recombinant isoQC was analyzed applying a kinetic assay that is based on consumption of NADH in a coupled reaction [52] (Fig. 2d)
Summary
Amyloid pathology and neuroinflammation including activation of glial cells are key hallmarks of the neuropathology in brains of Alzheimer’s disease (AD) patients Both Abeta peptides and pro-inflammatory cytokines/ chemokines are reported to interfere with neuronal survival and with proper synaptic function, resulting in cognitive decline [6, 20, 21, 62]. C In coronal sections, some brain regions with high expression levels of isoQC can be distinguished These include piriform 1 entorhinal 3 and pyramidal layer V 6 cortices, hippocampal structures such as indusium griseum 2, Cornu ammonis 1–4 and dentate gyrus 5, as well as habenular 4 and Edinger–Westphal 7 nuclei, locus coeruleus 8, cochlear nucleus 9 and Purkinje cells of the cerebellum 10. PGlu-modified Abeta peptides in brains of AD patients and transgenic mouse models were reported to be closely associated with [11C]Pittsburgh Compound-B (PIB) autoradiographic signals [28]
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