title: Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer's disease.
abstract: Brains of Alzheimer's disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Aβ was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Aβ and pGlu-Aβ concentrations were quantified by ELISA. Data on QC expression and Aβ peptide concentrations were correlated with each other and with the Mini-Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Aβ deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Aβ aggregates, but not of unmodified Aβ peptides. Elevated pGlu-Aβ load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Aβ. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Aβ formation.
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Morawski
authors.affiliation: Probiodrug AG, Halle/S., Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Kreuzberger
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Waniek
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Jäger
authors.affiliation: Probiodrug AG, Halle/S., Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.affiliation: Probiodrug AG, Halle/S., Germany Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.affiliation: Probiodrug AG, Halle/S., Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arendt
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Hartlage-Rübsamen
authors.affiliation: Probiodrug AG, Halle/S., Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Roßner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D018728:Entorhinal Cortex / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009474:Neurons / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid
keywords: Alzheimer's disease; Mini-Mental State Examination; entorhinal cortex; glutaminyl cyclase; pyroglutamate-Aβ