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

Neuropharmacology
Gerhard RammesChris G Parsons

Abstract

Aβ1-42 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 Aβ1-42 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 Aβ1-42 and 1-40 (Aβ1-40) 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 IC50s of 2, 9, 2 and 35 nM, respectively whilst having no effect on baseline AMPA receptor mediated fEPSPs. Aβ1-43 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 IC50 was 20 nM. A low concentration (10 nM)...Continue Reading

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