Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Background: Intracellular amyloid-beta oligomers (iA{beta}o) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iA{beta}o) and synthetic (iA{beta}o) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro, ex vivo and in vivo. Results: Starting from 500 pM, iA{beta}o rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iA{beta}o, indicating that iA{beta}o can increase network excitability at a distance. Current-clamp recordings suggested that iA{beta}o increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iA{beta}o causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.