Spatiotemporal immunolocalisation of REST in the brain of healthy ageing and Alzheimer’s disease rats

Abstract

In the brain, REST (Repressor Element-1 Silencing Transcription factor) is a key regulator of neuron cell-specific gene expression. Nuclear translocation of neuronal REST has been shown to be neuroprotective in a healthy ageing context. In contrast, inability to upregulate nuclear REST is thought to leave ageing neurons vulnerable to neurodegenerative stimuli, such as Alzheimer's disease (AD) pathology. Hippocampal and cortical neurons are known to be particularly susceptible to AD-associated neurodegeneration. However, REST expression has not been extensively characterised in the healthy ageing brain. Here, we examined the spatiotemporal immunolocalisation of REST in the brains of healthy ageing wild-type Fischer-344 and transgenic Alzheimer's disease rats (TgF344-AD). Nuclear expression of REST increased from 6 months to 18 months of age in the hippocampus, frontal cortex and subiculum of wild-type rats, but not in TgF344-AD rats. No changes in REST were measured in more posterior cortical regions or in the thalamus. Interestingly, levels of the presynaptic marker synaptophysin, a known gene target of REST, were lower in CA1 hippocampal neurons of 18-month TgF344-AD rats compared to 18-month wild-types, suggesting that elevated nuclear REST may protect against synapse loss in the CA1 of 18-month wild-type rats. High REST expression in ageing wild-type rats did not, however, protect against axonal loss nor against astroglial reactivity in the hippocampus. Taken together, our data confirm that changes in nuclear REST expression are context-, age-and brain region-specific. Moreover, key

All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer’s disease

“…Other studies have shown an increased cytoskeleton hypertrophy or increased complexity of astrocytes near Aß plaques using GFAP immunolabeling in the hippocampus of 6, 12, and 18-month-old TgF344 male and female rats [Swedish mutation in APP and humanized PSEN1 (Cohen et al, 2013)] (Mampay et al, 2020), in the dentate gyrus and hippocampus CA1 of 18-month-old 3xTg male mice (Olabarria et al, 2010) and in the cerebral cortex of 3, 6 and 12-month-old APP-PS1 mice (increase in volume and process length) (Li et al, 2020). A sex-specific increase in the abundance of hypertrophic astrocytes in 7-9 month-old APP-PS1 female compared to male mice was observed in the outer molecular layer of the dentate gyrus (Richetin et al, 2017).…”