| Abstract Body | The RE1-silencing transcription factor (REST) has been strongly implicated in Alzheimer’s disease (AD), healthy ageing and longevity. There is a clear need to better understand the exact mechanisms that mediate that role. Here we study the role of REST in a series of AD-related phenotypes in the mouse brain.
We have previously generated a conditional knockout (cKO) mouse model, lacking Rest in the adult forebrain. Immunohistochemistry and Western blot were used to evaluate the effect of REST on neuronal and astrocytic markers, proteins encoded by immediate-early genes and key proteins involved in tau phosphorylation. Furthermore, RNA-Seq was used to study the whole genome effect of REST.
Quantification of neuronal nuclei and astrocytes on brain sections labelled with appropriate markers (NeuN and GFAP, respectively) revealed no major neurodegeneration or astrocytic activation in Rest cKO mice. Interestingly, levels of proteins involved in the phosphorylation of tau, such as glycogen synthase kinase-3beta (GSK-3β) and p35/p25 (activators of CDK5), were found significantly increased in Rest cKO mice. No major differences were observed in the levels of the presynaptic protein synaptophysin; however, there is evidence of reduced levels of the postsynaptic protein PSD95 in Rest cKO mice. Preliminary RNA-seq results, including gene ontology, gene set enrichment analyses and protein-protein interaction analysis, indicate that neuronal activity and protection are decreased in the absence of REST.
Expression of certain key proteins involved in one of the hallmarks of Alzheimer’s disease, tau phosphorylation, and in postsynaptic activity appear to be altered in the brain of Rest cKO mice. Our results suggest no major neurodegenerative phenotype when REST is inactivated in the adult mouse brain, although some AD-affected pathways involved in neuronal function might be affected in our mouse model.
|
|---|
