Repressor Element 1 Silencing Transcription Factor (REST) Governs Microglia-Like BV2 Cell Migration via Progranulin (PGRN)

Tongya Yu,Yuzhen Xu,Xueyuan Liu,Hui Quan,Yingying Lin,Yunxiao Dou,Yanxin Zhao,Feihong Wang,Fushun Wang

doi:10.1155/2020/8855822

Abstract

Microglia activation contributes to Alzheimer's disease (AD) etiology, and microglia migration is a fundamental function during microglia activation. The repressor element-1 silencing transcription factor (REST), a powerful transcriptional factor, was found to play a neuroprotective role in AD. Despite its possible role in disease progression, little is known about whether REST participates in microglia migration. In this study, we aimed to explore the function of REST and its molecular basis during microglia migration under Aβ1-42-treated pathological conditions. When treated by Aβ1-42 REST was upregulated through JAK2/STAT3 signal pathway in BV2 cells. And transwell coculture system was used to evaluate cell migration function of microglia-like BV2. Small interfering RNA (siRNA) targeting progranulin (PGRN) were delivered into BV2 cells, and results showed that PGRN functions to promote BV2 migration. REST expression was inhibited by sh-RNA, which induced BV2 cell migration obviously. On the contrary, REST was overexpressed by REST recombinant plasmid transfection, which repressed BV2 cell migration, indicating that REST may act as a repressor of cell migration. To more comprehensively examine the molecular basis, we analyzed the promoter sequence of PGRN and found that it has the potential binding site of REST. Moreover, knocking-down of REST can increase the expression of PGRN, which confirms the inhibiting effect of REST on PGRN expression. Further detection of double luciferase reporter gene also confirmed the inhibition of REST on the activity of PGRN promoter, indicating that REST may be an inhibitory transcription factor of PGRN which governs microglia-like BV2 cell migration. In conclusion, the present study demonstrates that transcription factor REST may act as a repressor of microglia migration through PGRN.

Highlights

Alzheimer’s disease, the first leading cause of senile dementia, is characterized by amyloid-β deposition and tau hyperphosphorylation
We further show that repressor element-1 silencing transcription factor (REST) regulated microglia migration through PGRN
These results indicated that compared with Aβ1-42 itself, impaired neurons are more likely to promote microglia migration

Summary

Introduction

Alzheimer’s disease, the first leading cause of senile dementia, is characterized by amyloid-β deposition and tau hyperphosphorylation. Increasing evidence indicates that over activation of microglia plays an important role in the development of Alzheimer’s disease [1]. The resident immune cell of the brain, are considered to be the first line defense and respond quickly to infectious, inflammatory, and pathophysiological stimuli [2, 3]. As the guardian of the central nervous system, microglia are constantly sampling their environment to maintain homeostasis and respond to immune challenges [4]. The migration of microglia is mediated by the interaction of chemokine and its receptor. Published data showed that progranulin (PGRN), a multifunctional growth factor expressed in various tissues, may act as a chemoattractant for microglia that over expression of progranulin in Neural Plasticity

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