title: Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms.
abstract: In the hippocampal formation of Alzheimer's disease (AD) patients, both focal and diffuse deposits of Aβ peptides appear in a subregion- and layer-specific manner. Recently, pyroglutamate (pGlu or pE)-modified Aβ peptides were identified as a highly pathogenic and seeding Aβ peptide species. Since the pE modification is catalyzed by glutaminyl cyclase (QC) this enzyme emerged as a novel pharmacological target for AD therapy. Here, we reveal the role of QC in the formation of different types of hippocampal pE-Aβ aggregates. First, we demonstrate that both, focal and diffuse pE-Aβ deposits are present in defined layers of the AD hippocampus. While the focal type of pE-Aβ aggregates was found to be associated with the somata of QC-expressing interneurons, the diffuse type was not. To address this discrepancy, the hippocampus of amyloid precursor protein transgenic mice was analysed. Similar to observations made in AD, focal (i.e. core-containing) pE-Aβ deposits originating from QC-positive neurons and diffuse pE-Aβ deposits not associated with QC were detected in Tg2576 mouse hippocampus. The hippocampal layers harbouring diffuse pE-Aβ deposits receive multiple afferents from QC-rich neuronal populations of the entorhinal cortex and locus coeruleus. This might point towards a mechanism in which pE-Aβ and/or QC are being released from projection neurons at hippocampal synapses. Indeed, there are a number of reports demonstrating the reduction of diffuse, but not of focal, Aβ deposits in hippocampus after deafferentation experiments. Moreover, we demonstrate in neurons by live cell imaging and by enzymatic activity assays that QC is secreted in a constitutive and regulated manner. Thus, it is concluded that hippocampal pE-Aβ plaques may develop through at least two different mechanisms: intracellularly at sites of somatic QC activity as well as extracellularly through seeding at terminal fields of QC expressing projection neurons.
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Hartlage-Rübsamen
authors.forename: Markus
authors.initials: M
authors.lastname: Morawski
authors.forename: Alexander
authors.initials: A
authors.lastname: Waniek
authors.forename: Carsten
authors.initials: C
authors.lastname: Jäger
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zeitschel
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schliebs
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Steffen
authors.initials: S
authors.lastname: Rossner
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000493:pharmacokinetics; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000493:pharmacokinetics; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D019881:Aminoacyltransferases / Q000172:deficiency / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001345:Autoradiography / Q000379:methods; D002478:Cells, Cultured; D004082:Dihydroalprenolol / Q000493:pharmacokinetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011189:Potassium Chloride / Q000494:pharmacology; D011224:Prazosin / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D015016:Yohimbine / Q000493:pharmacokinetics
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011941:Receptors, Adrenergic; C485184:enhanced green fluorescent protein; D014316:Tritium; D049452:Green Fluorescent Proteins; D015016:Yohimbine; D004082:Dihydroalprenolol; D011189:Potassium Chloride; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid; D011224:Prazosin