RESUMO
Alzheimer's disease severely compromises cognitive function. One of the mechanisms to explain the pathology of Alzheimer's disease has been the hypotheses of amyloid-pore/channel formation by complex Aß-aggregates. Clinical studies suggested the moderate alcohol consumption can reduces probability developing neurodegenerative pathologies. A recent report explored the ability of ethanol to disrupt the generation of complex Aß in vitro and reduce the toxicity in two cell lines. Molecular dynamics simulations were applied to understand how ethanol blocks the aggregation of amyloid. On the other hand, the in silico modeling showed ethanol effect over the dynamics assembling for complex Aß-aggregates mediated by break the hydrosaline bridges between Asp 23 and Lys 28, was are key element for amyloid dimerization. The amyloid pore/channel hypothesis has been explored only in neuronal models, however recently experiments suggested the frog oocytes such an excellent model to explore the mechanism of the amyloid pore/channel hypothesis. So, the used of frog oocytes to explored the mechanism of amyloid aggregates is new, mainly for amyloid/pore hypothesis. Therefore, this experimental model is a powerful tool to explore the mechanism implicates in the Alzheimer's disease pathology and also suggests a model to prevent the Alzheimer's disease pathology.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Etanol/química , Modelos Moleculares , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Animais , Cálcio/metabolismo , Humanos , Oócitos/química , Oócitos/metabolismo , Xenopus/crescimento & desenvolvimentoRESUMO
GABAρ1 receptors are highly expressed in bipolar neurons of the retina and to a lesser extent in several areas of the central nervous system (CNS), and dopamine and serotonin are also involved in the modulation of retinal neural transmission. Whether these biogenic amines have a direct effect on ionotropic GABA receptors was not known. Here, we report that GABAρ1 receptors, expressed in X. laevis oocytes, were negatively modulated by dopamine and serotonin and less so by octopamine and tyramine. Interestingly, these molecules did not have effects on GABA(A) receptors. 5-Carboxamido-tryptamine and apomorphine did not exert evident effects on any of the receptors. Schild plot analyses of the inhibitory actions of dopamine and serotonin on currents elicited by GABA showed slopes of 2.7 ± 0.3 and 6.1 ± 1.8, respectively, indicating a noncompetitive mechanism of inhibition. The inhibition of GABAρ1 currents was independent of the membrane potential and was insensitive to picrotoxin, a GABA receptor channel blocker and to the GABAρ-specific antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl phosphinic acid (TPMPA). Dopamine and serotonin changed the sensitivity of GABAρ1 receptors to the inhibitory actions of Zn(2+). In contrast, La(3+) potentiated the amplitude of the GABA currents generated during negative modulation by dopamine (EC(50) 146 µM) and serotonin (EC(50) 196 µM). The functional role of the direct modulation of GABAρ receptors by dopamine and serotonin remains to be elucidated; however, it may represent an important modulatory pathway in the retina, where GABAρ receptors are highly expressed and where these biogenic amines are abundant.