RESUMEN
Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals that ingest low amounts of alcohol. Also, it has been found that moderate consumption of ethanol might protect against ß-amyloid (Aß) toxicity. However, the mechanism underlying its potential neuroprotection is largely unknown. In the present study, we found that ethanol improved the cognitive processes of learning and memory in 3xTgAD mice. In addition, we found that a low concentration of ethanol (equivalent to moderate ethanol consumption) decreased the binding of Aß (1 and 5 µM) to neuronal membranes and, consequently, its synaptotoxic effect in rat hippocampal and cortical neurons under acute (30 minutes) and chronic (24 hours) incubation conditions. This effect appears to be exerted by a direct action of ethanol on Aß because electron microscopy studies showed that ethanol altered the degree of Aß aggregation. The action of ethanol on Aß also prevented the peptide from perforating the neuronal membrane, as assayed with patch clamp experiments. Taken together, these results contribute to elucidating the mechanism by which low concentrations of ethanol protect against toxicity induced by Aß oligomers in primary neuronal cultures. These results may also provide an explanation for the decrease in the risk of Alzheimer's disease in people who consume moderate doses of alcohol.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Etanol/administración & dosificación , Etanol/farmacología , Hipocampo/metabolismo , Hipocampo/patología , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ratones Transgénicos , Fármacos Neuroprotectores , Ratas Sprague-DawleyRESUMEN
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.