Regulation of tau‐phosphorylation and other Alzheimer’s disease‐associated phenotypes in REST conditional knockout mice

Tomás, Mariana Santos Vidal, Benestad, Johan Lafond, Keime, Céline, Buckley, Noel and Beglopoulos, Vassilios orcid iconORCID: 0000-0002-2736-4221 (2023) Regulation of tau‐phosphorylation and other Alzheimer’s disease‐associated phenotypes in REST conditional knockout mice. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 19 (S13). ISSN 1552-5260

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Official URL: https://doi.org/10.1002/alz.079146

Abstract

AbstractBackgroundThe RE1‐silencing transcription factor (REST) has been strongly implicated in Alzheimer’s disease (AD), healthy ageing and longevity, and there is a clear need to understand better 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.MethodWe have previously generated a conditional knockout (cKO) mouse model, lacking Rest in the postnatal forebrain. Immunohistochemistry and Western blot were used to evaluate the effect of REST on neuronal, synaptic and astrocytic markers and key proteins involved in tau phosphorylation. Furthermore, RNA‐Seq (including gene ontology, gene set enrichment and protein‐protein interaction analyses) was used to study the effect of REST inactivation at the transcriptome.ResultQuantification of labelled neuronal nuclei on brain sections revealed no major neurodegeneration in Rest cKO mice. However, mild phenotypes of dendritic degeneration and as astrocytic activation were suggested. The levels of an important postsynaptic protein, PSD‐95, appeared reduced in the brain of 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), as well as the levels of phosphorylated tau, were found increased in the brain of Rest cKO mice. RNA‐seq results suggest that postnatal inactivation of REST down‐regulates synaptic activity and neuronal pathways, while triggering an immune response.ConclusionOur results suggest dysregulation of one of the biochemical hallmarks of Alzheimer’s disease, tau phosphorylation, and of synaptic and neuronal pathways, as well as an immune response, when REST is inactivated in the adult mouse brain.


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