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

Aß1-42 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 Aß1-42 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 ß-amyloid species, 1-42 Aß1-42 and 1-40 (Aß1-40) as well as post-translationally modified forms such as pyroglutamate-modified amyloid-(AßpE3) and nitrated Aß (3NTyr10-Aß), 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. Aß1-43 had no effect. Interestingly, the combination of all Aß species did not result in any synergistic or additive inhibitory effect on LTP - the calculated pooled Aß species IC50 was 20 nM. A low concentration (10 nM) of the GLUN2B receptor antagonist Radiprodil restored LTP in the presence of Aß1-42, 3NTyr10-Aß, Aß1-40, but not AßpE3. In contrast to AMPA receptor mediated fEPSPs, all different ß-amyloid species tested at 50 nM supressed baseline NMDA-EPSC amplitudes. Similarly, all different Aß species tested decreased spine density. As with LTP, Radiprodil (10 nM) reversed the synaptic toxicity of Aß species but not that of AßpE3. These data do not support the enhanced toxic actions reported for some Aß species such as AßpE3, nor synergistic toxicity of the combination of different Aß species. However, whilst in our hands AßpE3-42 was actually less toxic than Aß1-42, its effects were not reversed by Radiprodil indicating that the target receptors/subunits mediating such synaptotoxicity may differ between the different Aß species tested.

Involvement of GluN2B subunit containing N-methyl-d-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aß) in murine models of Alzheimer's disease (AD).

To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9-18 months) were tested for spatiotemporal activity propagation and long-term potentiation (LTP) induction. CA1-LTP induced by high frequency stimulation (HFS; 100 Hz/1s) was not different in all genotypes. Aß1-42 (50 nM)-application reduced potentiation of fEPSP in WT and hetGluN2B/mAPP mice, LTP in mAPP and hetGluN2B mice was not affected. For VSDI a fast depolarization signal was evoked in the granule cell layer and propagation was analysed in hippocampal CA3 and CA1 region before and after theta stimulation (100pulses/5 Hz). LTP was not significantly different between all genotypes. In mAPP mice θ-stim produced an epileptiform activity reflected in a pronounced prolongation of the FDS compared to the other genotypes. In slices of hetGluN2B/mAPP and GluN2B mice, however, these parameters were similar to WT mice indicating a reversal effect of the attenuated GluN2B expression. The induction of a hetGluN2B mutation in the mAPP reversed some pathophysiological changes on hippocampal LTP and provide further evidence for the involvement of the glutamatergic system in AD and emphasize the GluN2B subunit as a potential target for AD treatment.