lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer’s disease

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 Aβ-degrading enzymes. The mouse model of AD and the cell model induced by Aβ 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-1β, TNFα, IL-8, and Aβ42 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 Aβ-induced neuronal inflammation and damage. LncRNA XIST affected the expression of Aβ-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 Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in AD.

Keywords:

• lncRNA XIST
• NEP
• epigenetic repression
• Alzheimer’s disease

Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Ethical approval

Animal experiments were approved by Experimental Animal Ethics Committee of the Affiliated Hospital of Nanjing University of Chinese Medicine (2020DW-08–02). This article does not contain any studies with human participants performed by any of the authors.

Author contributions

XWY: conceptualization; funding acquisition; HJL: writing-original draft; YXH: data curation; resources; TM: methodology; formal analysis; JD: investigation; software; visualization; CC: project administration; supervision; validation; writing-review & editing. All authors have read and approved the final version of this manuscript to be published.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.