Genes y mecanismos implicados en la toxicida neuronal inducida por el peptido amiloide y por priones

Resumen

Alzheimer and Prion diseases are a group of neurodegenerative disorders characterized by astrocytosis and progressive neuronal degeneration. As a causative agent, prions and b-amyloid proteins have been intensely investigated in different in vitro and in vivo experimental models. However, the mechanisms and pathways involved in prion- or b-amyloid-induced neurological dysfunction are poorly understood. Compelling evidence suggest that misfolded prions and b-amyloid-protein aggregates, play an important role in cell dysfunction and tissue damage, leading to disease in both patologies. Prion protein (Prion diseases) and b-amyloid (Alzheimer's disease) are proteins that trigger disease when they get misfolded. Several lines of evidence suggest that a defective protein folding is a central event in both Alzheimer's and Prion disease. Although the two disorders are very different clinically, neuropathologically, and biochemically, the molecular event that may trigger the disease process appears to be the same: the formation of an altered protein conformer, the amyloid aggregates, composed of a high content of beta-sheet structure. Several mechanisms have been proposed to be involved in the amyloidinduced neurotoxicity; among others it has been suggested that amyloid peptides exerts their toxic effect mainly by activating the surrounding microglia population, which in turn induces the synthesis and release of preapoptotic and pro-inflammatory factors. In addition, a direct effect of b-amyloid and prions on neurons has also been described. In fact, the precise mechanisms involved in the b-amyloid and prions-induced neurotoxicity have not yet been definitely clarified. To characterize the effects directly induced on neurons, we have analyzed the gene expression profile induced by synthetic peptides corresponding to the most neurotoxic regions of prions and b-amyloid peptides, PrP 106-126 and Ab 25-35 respectively. Using an Array HG-U133 plus 2.0 and quantitative reverse transcriptasepolymerase chain reaction method, we have analysed in SH-SY5Y cells the effects of these peptides. Our results show that addition of these peptides to the neuronal culture specifically changes the expression of a relative high number of genes, modifying several pathways and biological processes in a common way and causes progressive neuronal death even in the absence of microglia. These results may be useful as novel therapeutic approaches for Alzheimer¿s and Prion diseases.