Effects of different forms of amyloid β-peptide on synaptic function.

Introduction: In early stages of Alzheimer’s disease, that precede plaque formation and neuronal death, cognitive deficits are likely the result of synaptic function impairment. The key initiating pathogenic event is the accumulation of neurotoxic aggregates of amyloid β-peptide (Aβ) in hippocampus and cortex. We previously demonstrated that the redox state of methionine in position 35 (Met35) plays a critical role in Aβ toxicity. Objective: To determine whether oxidation of Met35 also influences Aβ synaptotoxicity we investigated the effects of 20-min lasting perfusion with 200 nM AβWT and its oxidized analogues (AβMet35(O), AβMet35(O2)) on synaptic transmission and plasticity, and on synaptophysin (Syn) expression. Methods: We performed electrophysiological experiment on hippocampal brain slices and autaptic neurons to study the long-term potentiation (LTP) and synaptic transmission. We also studied Syn density as the ratio between Syn fluorescence intensity and MAP2 labeled area by confocal microscopy. Results: In control slices, 60 min after tetanus fEPSP amplitude (A) and slope (S) were increased by 138% and 132% of baseline, respectively. This potentiation was significantly lower after AβWT treatment (A: +72%; S: +68%; P<0.001) whereas no changes in LTP were observed in slices exposed to AβMet35(O). Surprisingly, AβMet35(O2) reduced the synaptic plasticity to the same level as AβWT. In autaptic microcultures, AβWT and AβMet35(O2) significantly reduced the amplitude of EPSCs evoked by action potentials and mEPSC frequency (P<0.05) whereas AβMet35(O) had no effects on basal synaptic transmission. Finally, AβWT and AβMet35(O2) significantly reduced Syn density while AβMet35(O) did not affect presynaptic terminals. Conclusion: Our results indicate that the chemical state of Met35 plays a key role in Aβ- induced: (i) synaptic depression, (ii) inhibition of synaptic plasticity and (iii) alterations in the expression of proteins relevant for the synaptic function.