lncRNA XIST induces A accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer's disease
JOURNAL OF NEUROGENETICS(2022)
Abstract
Alzheimer's disease (AD) is the leading cause of dementia globally, but effective treatment is lacking. We aimed to explore lncRNA XIST role in AD and the mechanisms involved in the effect of changes in lncRNA XIST on the expression of A beta-degrading enzymes. The mouse model of AD and the cell model induced by A beta were established. LncRNA XIST, IDE, NEP, Plasmin, ACE, EZH2 expressions and distribution of XIST in the nucleus and cytoplasm were detected by qRT-PCR. Inflammatory cytokines IL-6, IL-1 beta, TNF alpha, IL-8, and A beta 42 levels were detected by ELISA. TUNEL was used to measure brain tissue damage. Cell proliferation was detected by CCK-8 assay. Flow cytometry detected cell apoptosis. RIP validated the combination of XIST and EZH2. ChIP verified that XIST recruits EZH2 to mediate enrichment of HEK27me3 in the NEP promoter region. The protein expression in brain tissues and cells was detected by Western blot. The expression of lncRNA XIST was increased in AD mice and cell models. Inflammation and injury of nerve cells occurred in AD mice and cell models. The knockdown of lncRNA XIST alleviated A beta-induced neuronal inflammation and damage. LncRNA XIST affected the expression of A beta-degrading enzyme NEP, and lncRNA XIST was negatively correlated with NEP expression in AD mice. LncRNA XIST regulated NEP expression partly through epigenetic regulation by binding with EZH2. LncRNA XIST mediated neuronal inflammation and injury through epigenetic regulation of NEP. Overall, our study found that lncRNA XIST induced A beta accumulation and neuroinflammation by the epigenetic repression of NEP in AD.
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Key words
lncRNA XIST,NEP,epigenetic repression,Alzheimer's disease
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