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Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain‐derived (h‐iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAβo 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 iAβo, indicating that iAβo can increase network excitability at a distance. Current‐clamp recordings suggested that iAβo increased neuronal excitability via AMPA‐driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAβo 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., In the presence of iAβo, PKC is activated (a), which in turn allows the production of nitric oxide (NO) at the post‐synaptic level, increasing the release of neurotransmitters (b) (evidenced as an increase in the frequency of mPSC). PKC also increases AMPA receptor current (c), increasing post‐synaptic depolarization and neuronal excitability (d). Finally, iAβo increases synchronization NO production in nearby neurons that do not have iAβo (e).

A major characteristic of Alzheimer's disease is the presence of amyloid beta (Aβ) oligomers and aggregates in the brain. Aβ 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-Aβ compound having the sequence of the glycine zipper region of the C-terminal of Aβ (G33LMVG37). Docking and Förster resonance energy transfer experiments showed that G33LMVG37 interacts with Aβ at the C-terminal region, which is important for Aβ association and insertion into the lipid membrane. Furthermore, this pentapeptide interfered with Aβ aggregation, association, and perforation of the plasma membrane. The synaptotoxicity induced by Aβ after acute and chronic applications were abolished by G33LMVG37. These results provide a novel rationale for drug development against Alzheimer's disease.

A major feature of Alzheimer's disease is the accumulation of β-amyloid (Aβ) peptide in the brain. Recent studies have indicated that Aβ oligomers (Aβo) can interact with the cellular prion protein (PrPc). Therefore, this interaction might be driving some of Aβ toxic effects in the synaptic region. In the present study, we report that Aβo binds to PrPc in the neuronal membrane playing a role on toxic effects induced by Aβ. Phospholipase C-enzymatic cleavage of PrPc from the plasma membrane attenuated the association of Aβo to the neurons. Furthermore, an anti-PrP antibody (6D11) decreased the association of Aβo to hippocampal neurons with a concomitant reduction in Aβo and PrPc co-localization. Interestingly, this antibody blocked the increase in membrane conductance and intracellular calcium induced by Aβo. Thus, the data indicate that PrPc plays a role on the membrane perforations produced by Aβo, the increase in calcium ions and the release of synaptic vesicles that subsequently leads to synaptic failure. Future studies blocking Aβo interaction with PrPc could be important for the discovery of new therapeutic strategies for Alzheimer's disease.