Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes.

Jianjia Fan,Murray B Isman,Tom A Pfeifer,Wenchen Zhao,Jun-Hyung Tak,Bernard Van Den Hoven,Iva Kulic,Mark E Duggan,Yoko Shimizu,Shahab Zareyan,Cheryl L Wellington,Michael W Wood,Dong-Gyu Jo

doi:10.1371/journal.pone.0162384

Abstract

The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer’s Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 μM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRβ, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 μM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and results in severe impairments in memory [1]
ApoE plays an undeniable role in Alzheimer’s Disease (AD) pathogenesis and is among the most important targets to understand
In mouse models of AD-relevant amyloid deposition, direct liver x receptor (LXR)/retinoid x receptor (RXR) agonists increase lipidated Apolipoprotein E (apoE), improve memory performance, and can lower amyloid load, suggesting that increasing the levels of functional, lipid-carrying apoE is of therapeutic benefit [70,71,72]

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and results in severe impairments in memory [1]. Apolipoprotein E (apoE) plays a significant role in AD pathogenesis and is a promising candidate therapeutic target. ApoE is the most abundant apolipoprotein expressed in the central nervous system (CNS) [5, 6], where it is predominantly synthesized and secreted by astrocytes [7]. Following local production in the CNS, apoE is lipidated by the ATP-binding cassette transporter A1 (ABCA1) to form lipoprotein particles that resemble high-density lipoproteins (HDL) in size and buoyant density [8]. These particles transfer their lipid cargo to target cells via apoE receptors belonging to the low-density lipoprotein receptor (LDLR) family [9, 10]

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Results

Conclusion