Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate A Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice

Department of Molecular Psychiatry. Graduate School, University Medicine Goettingen, 37075 Goettingen, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2011; 286(6):4454-60. DOI: 10.1074/jbc.M110.185819
Source: PubMed


Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD.

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Available from: Thomas A Bayer, Oct 05, 2015
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    • "The modification of peptides by pGlu gained considerable interest due to its presence at the N-terminus of amyloid peptides such as ABri and Aβ (Jawhar et al., 2011a; Saul et al., 2013). In principle, the pGlu-modification has been shown to alter the biophysical properties of peptides by increasing their hydrophobicity, which may, in turn, increase the aggregation propensity, toxicity and stability against degradation by aminopeptidases (Jawhar et al., 2011b). The residue confers receptor binding and activation of, for example, CCL2, TRH or GnRH (Gong and Clark- Lewis, 1995; Goren et al., 1977; Sealfon et al., 1997). "
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    ABSTRACT: Secretory peptides and proteins are frequently modified by pyroglutamic acid (pE, pGlu) at their N-terminus. The modification is catalyzed by the glutaminyl cyclases QC and isoQC. Here, we decipher the roles of the isoenzymes by characterization of IsoQC-/- mice. These mice show a significant reduction of glutaminyl cyclase activity in brain and peripheral tissue, suggesting ubiquitous expression of the isoQC enzyme. An assay of substrate conversion in vivo reveals impaired generation of the pGlu-modified C-C chemokine ligand 2 (CCL2, MCP-1) in isoQC-/- mice. The formation was also impaired in primary neurons, which express significant levels of QC. Interestingly, however, the formation of the neuropeptide hormone thyrotropin-releasing hormone (TRH), assessed by immunohistochemistry and hormonal analysis of hypothalamic-pituitary-thyroid axis was not affected in isoQC-/-, which contrasts to QC-/-. Thus, the results reveal differential functions of isoQC and QC in the formation of the pGlu-peptides CCL2 and TRH. Substrates requiring extensive prohormone processing in secretory granules, such as TRH, are primarily converted by QC. In contrast, protein substrates such as CCL2 appear to be primarily converted by isoQC. The results provide a new example, how subtle differences in subcellular localization of enzymes and substrate precursor maturation might influence pGlu-product formation.
    Biological Chemistry 09/2015; DOI:10.1515/hsz-2015-0192 · 3.27 Impact Factor
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    • "Previous studies have demonstrated that biological or chemical inhibition of QC activity leads to amelioration of AD pathology, including improvement of the memory impairment [21] [29] [34]. However, the mechanism by which this phenomenon occurs remains unclear [29] [34] [35]. In this study, we attempted to confirm the improvement of amyloid pathogenesis both in vitro and in vivo by Fig. 4. QCI treatment induces ERK activation. "
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    ABSTRACT: Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid-β peptides (Aβ) are generated from amyloid-β precursor protein by consecutive catalysis by β- and γ-secretases. Diversely modified forms of Aβ have been discovered, including pyroglutamate Aβ (N3pE-42 Aβ). N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length Aβ. A previous study suggested that N3pE-42 Aβ formation is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE-42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation, namely modulation of γ-secretase activity.
    Journal of Alzheimer's disease: JAD 01/2015; 43(3):797-807. DOI:10.3233/JAD-141356 · 4.15 Impact Factor
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    • "In this mouse strain, QC overexpression resulted in elevated pGlu- A␤ levels, whereas QC knock-out diminished – but not completely abolished – the formation of pGlu-A␤ peptides (Jawhar et al., 2011). This finding indicates that QC is critically involved in the process of pGlu-A␤ formation but that alternative mechanisms possibly acting via isoQC may also play a role. "
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    ABSTRACT: Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) from glutamine precursors at the N-terminus of a number of peptide hormones, neuropeptides and chemokines. This post-translational modification stabilizes these peptides, protects them from proteolytical degradation or is important for their biological activity. However, QC is also involved in a pathogenic pGlu modification of peptides accumulating in protein aggregation disorders such as Alzheimer's disease and familial Danish and familial British dementia. Its isoenzyme (isoQC) was shown to contribute to aspects of inflammation by pGlu-modifying and thereby stabilizing the monocyte chemoattractant protein CCL2. For the generation of respective animal models and for pharmacological treatment studies the characterization of the mouse strain and brain region-specific expression of QC and isoQC is indispensible. In order to address this issue, we used enzymatic activity assays and specific antibodies to detect both QC variants by immunohistochemistry in nine different mouse strains. Comparing different brain regions, the highest enzymatic QC/isoQC activity was detected in ventral brain, followed by cortex and hippocampus. Immunohistochemical stainings revealed that QC/isoQC activity in cortex mostly arises from isoQC expression. For most brain regions, the highest QC/isoQC activity was detected in C3H and FVB mice, whereas low QC/isoQC activity was present in CD1, SJL and C57 mice. Quantification of QC- and isoQC-immunoreactive cells by unbiased stereology revealed a higher abundance of isoQC- than of QC-immunoreactive neurons in Edinger-Westphal nucleus and in substantia nigra. In the locus coeruleus, however, there were comparable densities of QC- and of isoQC-immunoreactive neurons. These observations are of considerable importance with regard to the selection of appropriate mouse strains for the study of QC/isoQC relevance in mouse models of neurodegeneration and neuroinflammation and for the testing of therapeutical interventions in these models.
    International Journal of Developmental Neuroscience 05/2014; DOI:10.1016/j.ijdevneu.2014.05.008 · 2.58 Impact Factor
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