Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Intracellular amyloid beta oligomer (iAßo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAßo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iAßo) and synthetic (iAßo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAßo 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)-associated fluorescence showed 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 iAßo, indicating that iAßo can increase network excitability at a distance. Current-clamp recordings suggested that iAßo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAßo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Inhibition of amyloid beta-induced synaptotoxicity by a pentapeptide derived from the glycine zipper region of the neurotoxic peptide.

A major characteristic of Alzheimer's disease is the presence of amyloid beta (Aß) oligomers and aggregates in the brain. Aß oligomers interact with the neuronal membrane inducing perforations, causing an influx of calcium ions and increasing the release of synaptic vesicles that leads to a delayed synaptic failure by vesicle depletion. Here, we identified a neuroprotective pentapeptide anti-Aß compound having the sequence of the glycine zipper region of the C-terminal of Aß (G33LMVG37). Docking and Förster resonance energy transfer experiments showed that G33LMVG37 interacts with Aß at the C-terminal region, which is important for Aß association and insertion into the lipid membrane. Furthermore, this pentapeptide interfered with Aß aggregation, association, and perforation of the plasma membrane. The synaptotoxicity induced by Aß after acute and chronic applications were abolished by G33LMVG37. These results provide a novel rationale for drug development against Alzheimer's disease.