Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain

Hartlage‐Rübsamen, Maike; Staffa, Katharina; Waniek, Alexander; Wermann, Michael; Hoffmann, Torsten; Cynis, Holger; Schilling, Stephan; Demuth, Hans‐Ulrich; Rößner, Steffen

doi:10.1016/j.ijdevneu.2009.08.007

Cited by 30 publications

(44 citation statements)

References 40 publications

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“…The secretion of QC from primary cells (Fig. 1) sup- ports its presence in the secretory pathway of neurons, which was also suggested recently by immunofluorescent double labelings of QC with compartment-specific marker proteins in mouse brain (33). The link between QC activity, neuropeptide maturation, and secretion is finally supported by the presence of GnRH and QC in serum, as shown here for the first time.…”

Section: Discussionsupporting

confidence: 86%

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Schilling

Kohlmann

Bäuscher

et al. 2011

Journal of Biological Chemistry

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Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development.

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Section: Discussionsupporting

confidence: 86%

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Schilling

Kohlmann

Bäuscher

et al. 2011

Journal of Biological Chemistry

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“…The antibody showed no significant differences in detecting mouse, rat and human QC in western blot analysis and immunohistochemistry, which appears conceivable considering a 85% protein sequence identity. Moreover, the specificity of the QC antiserum was previously shown by the robust labelling of mouse hypothalamic neurons, a known source of QC and of peptide hormones modified by QC, and by the absence of this labelling in brains from QC knock-out mice [18]. Additionally, the specificity of QC immunolabelling was validated by similar staining patterns obtained using a commercially available mouse anti-human QC antiserum (Abnova 1:500).…”

Section: Methodsmentioning

confidence: 85%

“…Thus, the enzymatic activity of QC appears to be a prerequisite for pE-Aβ peptide generation and, therefore, QC-expressing neurons may be at special risk for degeneration. In a recent study focussing on QC expression in telencephalic and diencephalic mouse brain regions, we observed QC in a subpopulation of lateral and paraventricular hypothalamic neurons and in a moderate number of GABAergic interneurons in the hippocampal molecular layer, in the hilus of the dentate gyrus and in all layers of the neocortex [18]. However, the proportion of QC neurons in cortex and hippocampus displaying pronounced immunoreactivity was rather low (0.5–2%), which may explain the lack of substantial neurodegeneration in these brain structures in APP transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

et al. 2010

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Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation.

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“…Antisera (against QC) were raised against recombinant full-length mouse QC (1301) and have been proven to recognize hQC (13).…”

Section: Methodsmentioning

confidence: 99%

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

Jawhar

Wirths

Schilling

et al. 2011

Journal of Biological Chemistry

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Pyroglutamate-modified A␤ (A␤pE3-42) 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 A␤pE3-42 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 A␤pE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant A␤pE3-42 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 A␤pE3-42 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 A␤pE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD. Alzheimer disease (AD)4 is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques composed of amyloid-␤ (A␤) and intracellular neurofibrillary tangles. The discovery that certain early onset familial forms of AD may be caused by enhanced levels of A␤ peptides has led to the hypothesis that amyloidogenic A␤ is intimately involved in the pathogenic process (1).Besides full-length A␤ 40 and 42 isoforms starting with an aspartate at position 1, a variety of different N-truncated A␤ peptides have been identified in AD brains. Ragged peptides including phenylalanine at position 4 of A␤ have been reported as early as 1985 by Masters et al. (2). In contrast, no N-terminal sequence could be obtained from cores purified in a SDS-containing buffer, which led to the assumption that the N terminus could be blocked (3, 4).The presence of A␤pE3 (N-terminally truncated A␤ starting with pyroglutamate) in AD brain was subsequently shown using mass spectrometry of purified A␤ peptides, explaining at least partially initial difficulties in sequencing A␤ peptides purified from human brain tissue (5). The authors reported that only 10 -15% of the total A␤ isolated by this method begins at position 3 with A␤pE3. Saido et al. (6) and others (7) subsequently showed that A␤pE3 represents a dominant fraction of A␤ peptides in AD brain.Overexpression of A␤pE3-42 in neurons of TBA2 transgenic mice triggers neuron loss and an associated neurological phenotype (8). N-terminal pE formation can be catalyzed by glutaminyl cyclase (QC) and is pharmacologically inhibited by QC inhibitors, b...

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Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain

Cited by 30 publications

References 40 publications

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

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

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