| Summary: | 碩士 === 高雄醫學大學 === 醫學研究所碩士班 === 94 === Aluminum (Al) is neurotoxic and has been implicated in several neurodegenerative diseases including Alzheimer’s disease (AD). Animals overexposed to Al exhibit pathological changes similar to those of AD. There are two neuropathological characteristics in AD that includes the formation of intracellular neurofibrillary tangles and the deposition of extracellular senile plaques. Beta-amyloid (Aβ) peptide is the principal composition of senile plaques, and is a proteolytic product of membranous amyloid precursor protein (APP). Evidence has shown that Al promotes formation and accumulation of Aβ. Since microglials in AD brains are activated that leads to subsequent imflammatory reactions, a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) are used clinically to reduce the progression of AD. Reducing the production of Aβ through inhibiting the Rho-ROCK signaling pathway is regarded as the underlying mechanism for the effects of NSAIDs on AD. In this study, an attempt was made to investigate whether Al induces neurotoxicity through activating the Rho-ROCK pathway and thus promoting the formation and accumulation of Aβ. Postnatal day 1 rats were used for the primary cortical neuronal cultures. Cell viability was evaluated by MTT assay and a significant decline in a time- and dose-dependent manner was observed after exposing cells to Al maltolate (Al(malt)3). The application of ROCK inhibitor reversed the adverse effect of Al(malt)3. Thioflavin T (ThT) staining revealed an increased intensity of fluorescence in the cytosol area after Al exposure, which indicated that more Aβ?? aggregates were formed intracellularly. The extents of Aβ aggregation in the culture medium were detected by ThT assay. An increase of ThT fluorescence was observed after Al exposure indicating that the extent of Aβ aggregation is increased. In contrast, the application of ROCK inhibitor prevents this effect of Al(malt)3. As for the level of sAPPα in the medium, negatively correlated to the level of Aβ, a decrease was found after Al exposure indicating an increase of the production of Aβ. Similarly, a recovery of the level of sAPPα was observed when the ROCK inhibitor was given. These results indicate that aluminum exerts its neurotoxic effects through activating the Rho-ROCK signaling pathway and thus promoting the production and accumulation of Aβ.
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