Overexpression of REST Causes Neuronal Injury and Decreases Cofilin Phosphorylation in Mice.

BACKGROUND

RE1-silencing transcription factor (REST) is known to silence target genes involved in synaptic plasticity and neuronal differentiation. Although previous studies implicate REST in neurodegenerative diseases, its function in the progression of Alzheimer's disease (AD) is uncertain.

OBJECTIVE

The aim of the present work was to explore the mechanisms of AD and determine whether and how REST was involved in the pathogenesis of AD.

METHODS

We investigated the differentially expressed genes and key transcription factors in AD using bioinformatics analysis. In addition, we assessed the expression of REST under the influence of AD-related factors. Mice overexpressing REST were generated and analyzed by proteomics analysis. We used transmission electron microscopy, Golgi-cox staining, immunohistochemistry, and western blotting to examine the impact of REST on neurons.

RESULTS

The results of bioinformatics analysis revealed REST as a hub transcriptional regulator in AD. We demonstrate that the mRNA expression of REST was significantly upregulated compared with that in the control groups, not only in AD patients but also in APP/PS1 transgenic mice, lipopolysaccharide-induced neuroinflammatory mice, and oxidative and glutamate stressed neurons. Using proteomics analysis, we showed that the upregulation of REST increased the expression of genes involved in apoptotic and mitochondrial pathways. Long-term overexpression of REST significantly reduced the number of dendritic spines and increased the mitochondrial defect and apoptosis. Reduction of the cofilin phosphorylation may be one of its mechanisms, and cofilin activity could be affected through the P38 MAPK/CREB signaling pathway.

CONCLUSION

These results demonstrated the possible mechanism underlying AD and indicated REST as a potential therapeutic target for AD.