LincRNA Plays a Role in the Effect of CYP46A1 Polymorphism in Alzheimer’s Disease – Related Pathology

Yang Chen,Ling Li,Fa-Ying Zhou,Yan-Jiang Wang,Hai Yang,Hua-Dong Zhou,Fan Zeng,Ze-Yan Peng,Hui-Yun Li,Le Chen

doi:10.3389/fnagi.2019.00381

Yang Chen, Ling Li + Show 8 more

Open Access

https://doi.org/10.3389/fnagi.2019.00381

Copy DOI

Abstract

Polymorphism of the cholesterol-24S-hydroxylase (CYP46A1) gene is thought to be a risk factor for Alzheimer’s disease (AD). A single nucleotide polymorphism (T/C) in intron 2, rs754203, has been confirmed to be implicated in AD. Rs754203 is located in the long intronic non-coding RNA (LincRNA) sequence, which has previously been shown to be involved in the pathology of many diseases. Thus, the present study aimed to investigate the role of LincRNA in the CYP46A1 gene expression and related AD pathology. SH-SY5Y cells with overexpressed TT or CC genotype CYP46A1 were used. Through RT-PCR, Western blot and ELISA assays, we found that LincRNA can affect the CYP46A1 gene expression and the production of 24-OHC and Aβ. Overexpression of LincRNA can significantly inhibit CYP46A1 expression and 24-OHC production, as well as increasing the Aβ expression level. Silencing of LincRNA confirmed the role that it plays in the regulation of CYP46A1, as well as the production of 24-OHC and Aβ. In addition, this effect was stronger in the A type LincRNA than in the G type LincRNA. Results from dual luciferase assays show that LincRNA inhibited the activity of the CYP46A1 gene promoter. This study indicates a possible novel role of LincRNA and provides a new way to look into the relationship between CYP46A1 polymorphism and AD pathology. This may identify a novel pathway through which to explore AD therapy.

Highlights

As the most common form of dementia, Alzheimer’s disease (AD) is affecting an increasing number of people, due to population growth and aging (Hodson, 2018)
To investigate whether long intronic non-coding RNA (LincRNA) can influence the expression of the CYP46A1 gene, whose polymorphism is thought to be involved in AD, we firstly constructed cell models of the different CYP46A1 genotypes in vitro through the transfection of SH-SY5Y cells
After transfection, CYP46A1 expression differed between cells that were transfected with the rs754203 TT and CC genotype, at both the mRNA and protein level

Summary

Introduction

As the most common form of dementia, Alzheimer’s disease (AD) is affecting an increasing number of people, due to population growth and aging (Hodson, 2018). APP, PSEN1, PSEN2, and APOE genes have all been shown to be related to AD occurrence. Because APOE is a major cholesterol carrier in the central nervous system, cholesterol metabolism is believed to play a role in AD pathology (Martins et al, 2009). When the production of cholesterol is increased or its exportation is decreased, it can accumulate in the brain, which can activate β-secretase and γ-secretase, resulting in amyloid β (Aβ) production. As the key regulator of cholesterol metabolism, the CYP46A1 gene is thought to be related to AD (Garcia et al, 2009). CYP46A1 may play a role in protecting neurons in the brain and decreased CYP46A1 expression may be involved in the pathology of AD

Methods

Results

Conclusion