Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade

Oligomeric β-amyloid peptide (Aβ) is one of the main neurotoxic agents of Alzheimer’s disease (AD). Oligomers associate to neuronal membranes, forming “pore-like” structures that cause intracellular calcium and neuro­transmitter dys­homeo­stasis, leading to synaptic failure and death. Through molecular screening targeting the C terminal region of Aβ, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuro­protective effects against Aβ toxicity. At micromolar concentrations, GBP antagonized peptide aggregation over time and reduced the Aβ absorbance plateau to 28% of control. In addition, GBP decreased Aβ association to membranes by almost half, and the effects of Aβ on intracellular calcium in hippocampal neurons were antagonized without causing effects on its own. Finally, we found that GBP was able to block the synapto­toxicity induced by Aβ in hippocampal neurons, increasing post-synaptic currents from 1.7 ± 0.9 to 4.2 ± 0.7 fC and mean relative fluorescence intensity values of SV2, a synaptic protein, from 0.7 ± 0.09 to 1.00 ± 0.08. The results show that GBP can interfere with Aβ-induced toxicity by blocking multiple steps, resulting in neuro­protection, which justifies advancing toward additional animal and human studies.