| Autor: |
González-Sanmiguel J; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., Burgos CF; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., Bascuñán D; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., Fernández-Pérez EJ; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., Riffo-Lepe N; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., Boopathi S; The Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca, Talca 3460000, Chile., Fernández-Pérez A; Department of Physics, University of Bío-Bío, Concepción 4030000, Chile., Bobadilla-Azócar C; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile., González W; The Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca, Talca 3460000, Chile.; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, Talca 3460000, Chile., Figueroa M; Laboratory of Molecular Biophysics, Department of Biochemistry and Molecular Biology, Universidad de Concepción, Concepción 4030000, Chile., Vicente B; Department of Psychiatry and Mental Health, Universidad de Concepcion, Concepción 4030000, Chile.; Program on Neuroscience, Psychiatry and Mental Health, Universidad de Concepcion, Concepción 4030000, Chile., Aguayo LG; Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción 4030000, Chile.; Program on Neuroscience, Psychiatry and Mental Health, Universidad de Concepcion, Concepción 4030000, Chile. |
| Abstrakt: |
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. |
