Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration

Background Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3–42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice. Results Expression of truncated Aβ(3–42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss. Conclusions ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models

Tradition und Moderne in der Literatur der Schweiz im 20. Jahrhundert

The papers in this volume show the presence of Gottfried Keller, the literary father figure of Swiss literature, in the texts of the Swiss authors from 1960ies, such as Otto F. Walter, Hugo Loetscher, Adolf Muschg, and Urs Widmer. Although these authors work in the democratic tradition of Switzerland and have an almost identificatory relationship to Keller, their role in the changed political life of the 20th century is completely different from that of their great literary model. The volume also contains studies on other Swiss literary classics, such as Robert Walser and Meinrad Inglin, as well as later authors, such as Max Frisch and Friedrich Dürrenmatt, Erica Pedretti, Thomas Hürlimann, Silvio Blatter, Peter Stamm, and Gertrud Leutenegger.In den in diesem Band zusammengetragenen Beiträgen wird die Präsenz des literarischen Übervaters der Schweizer Literatur, Gottfried Kellers, bei Autoren der 1960er Jahre wie Otto F. Walter, Hugo Loetscher, Adolf Muschg und Urs Widmer gezeigt. Diese engagierten Autoren, die sich zwar in die demokratische Tradition der Schweiz stellen und zu Keller in ein fast identifikatorisches Verhältnis treten, spielen anlässlich der veränderten politischen Öffentlichkeit im 20. Jahrhundert jedoch eine entschieden andere Rolle als ihr großes literarisches Vorbild. Aus der Sicht der Tradition und der Moderne werden im Hinblick auf die Schriftform und das Autobiographische sowie auf die Dorfwirklichkeit und die Karnevalisierung der Literatur die poetischen Auffassungen von zwei anderen Klassikern der Schweizer Literatur, von Robert Walser und Meinrad Inglin, in den Mittelpunkt der Betrachtungen und Diskussionen gerückt. Mit ihren Versuchen, die prekäre Nachkriegssituation in tragikomischen Dramen zu verarbeiten, kommen die beiden großen Beobachter der Auswirkungen des Faschismus, Frisch und Dürrenmatt zur Sprache. Vorgestellt wird Dürrenmatts politisches Engagement an seiner Auseinandersetzung mit dem „Vater der Wasserstoffbombe“, Edward Teller, die bei einer Fernsehdiskussion stattgefunden hatte. Der Einbruch der Moderne in die Familie wird an Autoren wie Erica Pedretti, Thomas Hürlimann und Silvio Blatter vorgeführt. Besonderes Augenmerk gilt jüngeren Autoren und Autorinnen wie Peter Stamm oder der zu Unrecht weniger bekannten Gertrud Leutenegger

Tradition und Moderne in der Literatur der Schweiz im 20. Jahrhundert

The papers in this volume show the presence of Gottfried Keller, the literary father figure of Swiss literature, in the texts of the Swiss authors from 1960ies, such as Otto F. Walter, Hugo Loetscher, Adolf Muschg, and Urs Widmer. Although these authors work in the democratic tradition of Switzerland and have an almost identificatory relationship to Keller, their role in the changed political life of the 20th century is completely different from that of their great literary model. The volume also contains studies on other Swiss literary classics, such as Robert Walser and Meinrad Inglin, as well as later authors, such as Max Frisch and Friedrich Dürrenmatt, Erica Pedretti, Thomas Hürlimann, Silvio Blatter, Peter Stamm, and Gertrud Leutenegger

Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration

Background Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3–42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice. Results Expression of truncated Aβ(3–42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss. Conclusions ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models

Glutaminyl cyclases as novel targets for the treatment of septic arthritis

Background. Septic arthritis is a severe and rapidly debilitating disease mainly caused by Staphylococcus aureus. Here, we assess the antiarthritic efficiency of glutaminyl cyclase (QC) inhibitors. Methods. Mice were inoculated with an arthritogenic amount of S. aureus intravenously or by local administration into the knee joint. Animals were treated with QC inhibitors (PBD155 and PQ529) via chow during the experiment. QC and isoQC knockout mice were also analyzed for arthritis symptoms after local administration of bacteria. Results. Both QC inhibitors significantly delayed the onset of clinical signs of arthritis, and inhibitors significantly decreased weight loss in treated animals. Following intraarticular injection of S. aureus, PBD155-treated mice had lower levels of synovitis and bone erosion, as well as less myeloperoxidase in synovial tissue. Fluorescence-activated cell sorter analysis revealed that PBD155 treatment affected the expression pattern of adhesion molecules, preventing the upregulation of cells expressing CD11b/CD18. Conclusion. The compounds investigated here represent a novel class of small molecular antiarthritic inhibitors. In our studies, they exerted strong antiinflammatory actions, and therefore they might be suited for disease-modifying treatment of infectious arthritis

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*

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