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Molecules 2018, 23(4), 924;

Immunohistochemical Evidence from APP-Transgenic Mice for Glutaminyl Cyclase as Drug Target to Diminish pE-Abeta Formation

Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany
Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle (Saale), Germany
Probiodrug AG, 06120 Halle (Saale), Germany
Institute of Pathology, Technical University of Munich, 81675 Munich, Germany
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 81377 Munich, Germany
Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany
Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
Institute for Advanced Study, Technical University of Munich, 85748 Garching, Germany
Authors to whom correspondence should be addressed.
Academic Editor: Stephan Schilling
Received: 20 March 2018 / Revised: 5 April 2018 / Accepted: 10 April 2018 / Published: 17 April 2018
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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Oligomeric assemblies of neurotoxic amyloid beta (Abeta) peptides generated by proteolytical processing of the amyloid precursor protein (APP) play a key role in the pathogenesis of Alzheimer’s disease (AD). In recent years, a substantial heterogeneity of Abeta peptides with distinct biophysical and cell biological properties has been demonstrated. Among these, a particularly neurotoxic and disease-specific Abeta variant is N-terminally truncated and modified to pyroglutamate (pE-Abeta). Cell biological and animal experimental studies imply the catalysis of this modification by the enzyme glutaminyl cyclase (QC). However, direct histopathological evidence in transgenic animals from comparative brain region and cell type-specific expression of transgenic hAPP and QC, on the one hand, and on the formation of pE-Abeta aggregates, on the other, is lacking. Here, using single light microscopic, as well as triple immunofluorescent, labeling, we report the deposition of pE-Abeta only in the brain regions of APP-transgenic Tg2576 mice with detectable human APP and endogenous QC expression, such as the hippocampus, piriform cortex, and amygdala. Brain regions showing human APP expression without the concomitant presence of QC (the anterodorsal thalamic nucleus and perifornical nucleus) do not display pE-Abeta plaque formation. However, we also identified brain regions with substantial expression of human APP and QC in the absence of pE-Abeta deposition (the Edinger-Westphal nucleus and locus coeruleus). In these brain regions, the enzymes required to generate N-truncated Abeta peptides as substrates for QC might be lacking. Our observations provide additional evidence for an involvement of QC in AD pathogenesis via QC-catalyzed pE-Abeta formation. View Full-Text
Keywords: Alzheimer’s disease; animal model; human APP expression; glutaminyl cyclase; pyroglutamate-Abeta Alzheimer’s disease; animal model; human APP expression; glutaminyl cyclase; pyroglutamate-Abeta

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Hartlage-Rübsamen, M.; Bluhm, A.; Piechotta, A.; Linnert, M.; Rahfeld, J.-U.; Demuth, H.-U.; Lues, I.; Kuhn, P.-H.; Lichtenthaler, S.F.; Roßner, S.; Höfling, C. Immunohistochemical Evidence from APP-Transgenic Mice for Glutaminyl Cyclase as Drug Target to Diminish pE-Abeta Formation. Molecules 2018, 23, 924.

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