Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression.

Dongmei Wu,Gongbo Li,Min Song,Yang Hu

doi:10.3389/fnagi.2021.634948

Abstract

Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of memory and other cognitive domains (Erkkinen et al, 2018)
Alamarblue assay was used to investigate whether the DDT doses in this study could trigger nonspecific cytotoxicity in H4 human neuroglioma cells (Figure 1A) and immortalized astrocytes (Figure 1B)
Because ATP-binding cassette transporter A1 (ABCA1) is a critical target of Liver X receptor α (LXRα) in brain, we proposed that LXRα may account for the DDT–ABCA1 molecular pathway

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of memory and other cognitive domains (Erkkinen et al, 2018). As the most common cause of dementia, AD affects about 30–46 million people worldwide (Caputo et al, 2020). Owing to the lack of effective treatments for dementia, the current goal of AD is early detection and treatment to prevent the exacerbation of cognitive impairment. Except for early-onset familial AD, the majority of late-onset AD is caused by the combination of genetic and environmental factors (Alzheimer’s Association, 2013). As one of the most persistent and widely used organochlorine pesticides, LXRα in DDT-Induced Aβ Deposition dichlorodiphenyltrichloroethane (DDT) seems to be a critical environmental factor for AD (van Wendel De Joode et al, 2001; Singh et al, 2013; Richardson et al, 2014). To screen out the potential targets of DDT-induced AD could be beneficial for the early detection and treatment of AD.

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Conclusion