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

Abstract

Aβ_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 IC₅₀s 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 IC₅₀ 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.

Keywords: Abeta; Alzheimer; GLUN2B; LTP; NMDA; Radiprodil; Spine density.