Abstract

Oligomeric beta-amyloid peptide (A beta) 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 A beta, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuroprotective effects against A beta toxicity. At micromolar concentrations, GBP antagonized peptide aggregation over time and reduced the A beta absorbance plateau to 28% of control. In addition, GBP decreased A beta association to membranes by almost half, and the effects of A beta 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 A beta in hippocampal neurons, increasing postsynaptic 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 A beta-induced toxicity by blocking multiple steps, resulting in neuro-protection, which justifies advancing toward additional animal and human studies.