Molecular mechanisms and brain morphology controlled by the transcription factor REST with relevance to Alzheimer’s disease

Becic, Dzenana (2020) Molecular mechanisms and brain morphology controlled by the transcription factor REST with relevance to Alzheimer’s disease. Masters thesis, University of Central Lancashire.

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Alzheimer’s disease (AD) is a major global health concern. Investigating the molecular mechanisms underlying AD will help develop new treatment strategies. The RE1-silencing transcription factor (REST) has been previously implicated in AD and is
neuroprotective in the human brain, a function which was found to be lost in those diagnosed with AD. However, the molecular mechanisms underlying this are unclear. This study has employed a previously generated genetically modified conditional knockout (cKO) mouse model lacking REST in the brain, with inactivation only in the postnatal forebrain, in excitatory neurons (from 2-3 weeks of age). Wielding histological analysis, the different regions of the hippocampus CA1, CA2, CA3 and the dentate gyrus (DG) have been studied, analysing a possible neurodegenerative phenotype. Analysis of samples using western blot experiments and antibodies, against various proteins has allowed the investigation of the potential molecular mechanisms involved and aimed to correlate previously observed RNA changes in the brain of Rest cKO mice to their translated protein level. The findings of this study have allowed some tentative conclusions to be drawn which help with understanding the role of REST in the brain. This study has shown a possible neurodegenerative effect in the CA2 region of the hippocampus in Rest cKO mice using immunohistochemical (IHC) analysis. Furthermore, regarding a social memory related phenotype
previously observed by the supervisor, a protein with a strong association to social memory impairment, Vasopressin V1B receptor (V1BR), was found to decrease in Rest cKO mice. Implying two possible conclusions regarding the CA2 region of the
hippocampus; a possible neurodegenerative phenotype or an impairment in social memory. Another principal finding revealed by this study showed lower levels of phosphorylated CREB (Ser133) protein in Rest cKO mice. This important finding could
suggest that a dysregulation in REST which leads to AD could occur due to a dysfunction in the mechanisms of CREB phosphorylation, associating memory loss to a lack of REST, a relationship which has not previously been made. The results from this study demonstrate the importance of research in REST and some features of neurodegeneration which should be further explored to allow potential therapeutic agents to be established.

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