title: Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes.
abstract: Recently, Aβ peptide variants with an N-terminal truncation and pyroglutamate modification were identified and shown to be highly neurotoxic and prone to aggregation. This modification of Aβ is catalyzed by glutaminyl cyclase (QC) and pharmacological inhibition of QC diminishes Aβ deposition and accompanying gliosis and ameliorates memory impairment in transgenic mouse models of Alzheimer's disease (AD). QC expression was initially described in the hypothalamus, where thyrotropin-releasing hormone (TRH) is one of its physiological substrates. In addition to its hormonal role, a novel neuroprotective function of TRH following excitotoxicity and Aβ-mediated neurotoxicity has been reported in the hippocampus. Functionally matching this finding, we recently demonstrated QC expression by hippocampal interneurons in mouse brain. Here, we detected neuronal co-expression of QC and TRH in the hippocampus of young adult wild type mice using double immunofluorescence labeling. This provides evidence for TRH being a physiological QC substrate in hippocampus. Additionally, in neocortex of aged but not of young mice transgenic for amyloid precursor protein an increase of QC mRNA levels was found compared to wild type littermates. This phenomenon was not observed in hippocampus, which is later affected by Aβ pathology. However, in hippocampus of transgenic - but not of wild type mice - a correlation between QC and TRH mRNA levels was revealed. This co-regulation of the enzyme QC and its substrate TRH was reflected by a co-induction of both proteins in reactive astrocytes in proximity of Aβ deposits. Also, in primary mouse astrocytes a co-induction of QC and TRH was demonstrated upon Aβ stimulation.
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Waniek
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Hartlage-Rübsamen
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Höfling
authors.affiliation: Institute for Medical Microbiology, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.affiliation: Fraunhofer Institute of Cell Therapy and Immunology IZI Leipzig, Department of Drug Design and Target Validation MWT Halle, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Fraunhofer Institute of Cell Therapy and Immunology IZI Leipzig, Department of Drug Design and Target Validation MWT Halle, Germany. Electronic address: hans-ulrich.demuth@izi.fraunhofer.de.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Germany. Electronic address: steffen.rossner@medizin.uni-leipzig.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Roßner
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001483:Base Sequence; D017931:DNA Primers; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D013379:Substrate Specificity; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017931:DNA Primers; D012333:RNA, Messenger; D013973:Thyrotropin-Releasing Hormone; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase
keywords: Amyloid pathology; Glutaminyl cyclase; Hippocampus; Thyrotropin-releasing hormone