RESUMEN
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 90â¯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 35â¯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 20â¯nM. A low concentration (10â¯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 50â¯nM supressed baseline NMDA-EPSC amplitudes. Similarly, all different Aß species tested decreased spine density. As with LTP, Radiprodil (10â¯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.