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Tytuł pozycji:

The NMDA receptor antagonist Radiprodil reverses the synaptotoxic effects of different amyloid-beta (Aβ) species on long-term potentiation (LTP).

Tytuł:
The NMDA receptor antagonist Radiprodil reverses the synaptotoxic effects of different amyloid-beta (Aβ) species on long-term potentiation (LTP).
Autorzy:
Rammes G; Department of Anaesthesiology, Technische Universität München, Munich, Germany. Electronic address: .
Seeser F; Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Mattusch K; Department of Anaesthesiology, Technische Universität München, Munich, Germany.
Zhu K; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Haas L; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Kummer M; Clinical Neuroscience Unit, Dept. of Neurology, University of Bonn, Germany.
Heneka M; Clinical Neuroscience Unit, Dept. of Neurology, University of Bonn, Germany.
Herms J; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Parsons CG; Non-Clinical Science, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany.
Źródło:
Neuropharmacology [Neuropharmacology] 2018 Sep 15; Vol. 140, pp. 184-192. Date of Electronic Publication: 2018 Aug 11.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Publication: Oxford : Pergamon Press
Original Publication: Oxford, New York, Pergamon.
MeSH Terms:
Acetamides/*pharmacology
Amyloid beta-Peptides/*antagonists & inhibitors
Excitatory Postsynaptic Potentials/*drug effects
Long-Term Potentiation/*drug effects
Peptide Fragments/*antagonists & inhibitors
Piperidines/*pharmacology
Amyloid beta-Peptides/toxicity ; Animals ; Dendritic Spines/drug effects ; Dose-Response Relationship, Drug ; Hippocampus/physiology ; Mice ; Peptide Fragments/adverse effects ; Peptide Fragments/toxicity
Contributed Indexing:
Keywords: Abeta; Alzheimer; GLUN2B; LTP; NMDA; Radiprodil; Spine density
Substance Nomenclature:
0 (3NTyr10-Ab peptide)
0 (AbetapE3 peptide)
0 (Acetamides)
0 (Amyloid beta-Peptides)
0 (Peptide Fragments)
0 (Piperidines)
0 (amyloid beta-protein (1-40))
0 (amyloid beta-protein (1-42))
5XGC17ZKUF (radiprodil)
Entry Date(s):
Date Created: 20180718 Date Completed: 20190220 Latest Revision: 20190319
Update Code:
20240105
DOI:
10.1016/j.neuropharm.2018.07.021
PMID:
30016667
Czasopismo naukowe
1-42 is well accepted to be a primary early pathogenic agent in Alzheimer's disease (AD). However, other amyloid peptides are now gaining considerable attention as potential key participants in AD due to their proposed higher neuronal toxicity. Impairment of the glutamatergic system is also widely accepted to be associated with pathomechanisms underlying AD. There is ample evidence that Aβ 1-42 affects GLUN2B subunit containing N-methyl-D-aspartate receptor function and abolishes the induction of long term potentiation (LTP). In this study we show that different β-amyloid species, 1-42 Aβ 1-42 and 1-40 (Aβ 1-40 ) as well as post-translationally modified forms such as pyroglutamate-modified amyloid-(AβpE3) and nitrated Aβ (3NTyr10-Aβ), when applied for 90 min to murine hippocampal slices, concentration-dependently prevented the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with IC 50 s of 2, 9, 2 and 35 nM, respectively whilst having no effect on baseline AMPA receptor mediated fEPSPs. Aβ 1-43 had no effect. Interestingly, the combination of all Aβ species did not result in any synergistic or additive inhibitory effect on LTP - the calculated pooled Aβ species IC 50 was 20 nM. A low concentration (10 nM) of the GLUN2B receptor antagonist Radiprodil restored LTP in the presence of Aβ 1-42 , 3NTyr10-Aβ, Aβ 1-40 , but not AβpE3. In contrast to AMPA receptor mediated fEPSPs, all different β-amyloid species tested at 50 nM supressed baseline NMDA-EPSC amplitudes. Similarly, all different Aβ species tested decreased spine density. As with LTP, Radiprodil (10 nM) reversed the synaptic toxicity of Aβ species but not that of AβpE3. These data do not support the enhanced toxic actions reported for some Aβ species such as AβpE3, nor synergistic toxicity of the combination of different Aβ species. However, whilst in our hands AβpE 3-42 was actually less toxic than Aβ 1-42 , its effects were not reversed by Radiprodil indicating that the target receptors/subunits mediating such synaptotoxicity may differ between the different Aβ species tested.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)

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