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

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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 brain structures involved in learning and memory display elevated REST expression in healthy ageing wild-type rats but not TgF344-AD rats.

Original languageEnglish
Pages (from-to)146-163
Number of pages18
JournalFEBS Open Bio
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
The authors would like to thank Christopher Thrasivoulou and Tim Robson (University College London) for technical support with fluorescence imaging. This work was supported by a University of Brighton PhD scholarship for M.M., an Irish Research Council PhD scholarship for M.V.E. (GOIPG/2015/2804), a PhD studentship from the BioImaging Institute, University of Manchester for A.M.C. and Output Enhancement Funding (OEF) from the University of Brighton for G.K.S. Purchase of TgF344‐AD rats was jointly supported by the European Union’s Seventh Framework Programme (FP7/2007‐2013) under grant agreement n° HEALTH‐F2‐2011‐278850 (INMiND) and Alzheimer Research UK network funds (H.B. grant holder). Breeding and maintenance costs for the TgF344‐AD rat colony were supported by the European Union’s Seventh Framework Programme (FP7/2007‐2013) under grant agreement n° HEALTH‐F2‐2011‐278850 (INMiND). E.M. is a recipient of Cancer Research UK Multidisciplinary [C57744/A22057] and CRUK‐UCL Centre [C416/A25145] Awards. E.M. and G.K.S. are grateful for funding from the Leverhulme Trust (RPG‐2018‐443).

Funding Information:
The authors would like to thank Christopher Thrasivoulou and Tim Robson (University College London) for technical support with fluorescence imaging. This work was supported by a University of Brighton PhD scholarship for M.M., an Irish Research Council PhD scholarship for M.V.E. (GOIPG/2015/2804), a PhD studentship from the BioImaging Institute, University of Manchester for A.M.C. and Output Enhancement Funding (OEF) from the University of Brighton for G.K.S. Purchase of TgF344-AD rats was jointly supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2011-278850 (INMiND) and Alzheimer Research UK network funds (H.B. grant holder). Breeding and maintenance costs for the TgF344-AD rat colony were supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2011-278850 (INMiND). E.M. is a recipient of Cancer Research UK Multidisciplinary [C57744/A22057] and CRUK-UCL Centre [C416/A25145] Awards. E.M. and G.K.S. are grateful for funding from the Leverhulme Trust (RPG-2018-443).

Publisher Copyright:
© 2020 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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