Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance By Decreasing Liver X Receptor Alpha Expression

Abnormal amyloid beta (A beta) 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 A beta clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt A beta clearance. Liver X receptor alpha (LXR alpha) 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 A beta clearance by targeting LXR alpha. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous A beta to evaluate A beta consumption. Meanwhile, cytotoxicity and LXR alpha expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXR alpha agonist T0901317 was determined in vitro. The interaction between DDT and LXR alpha was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit A beta clearance and decrease the levels of LXR alpha mRNA and LXR alpha protein. Moreover, DDT is supposed to strongly bind to LXR alpha and exert antagonistic effects on LXR alpha. In conclusion, this study firstly presented that DDT could inhibit LXR alpha expression, which would contribute to A beta clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.