Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons.

Huiling Gao,Cheng Li,Wei Zheng,He Xu

doi:10.3390/ijms222111582

Abstract

Hydrogen peroxide (H2O2)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H2O2. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H2O2. We propose that ApoE alleviates H2O2-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.

Highlights

The apolipoprotein E gene (APOE) has three major variants, APOE2, APOE3 and APOE4; so far APOE has been confirmed as the strongest genetic risk modifier for lateonset Alzheimer’s disease (AD), with the APOE4 conferring an increased risk and the APOE2 conferring a decreased risk relative to the common APOE3 allele [1,2]
Brain apolipoprotein E (ApoE) is a cholesterol transport protein secreted primarily by astrocytes that plays a vital role in transporting cholesterol and other lipids to neurons through ApoE receptors, a group of endocytic receptors belonging to low-density lipoprotein receptor (LDLR) family [3]
Our findings demonstrate that ApoE protects human Induced Pluripotent Stem Cells (iPSCs)-derived cortical neurons from H2O2-induced apoptosis via regulating Akt/Forkhead Box O3a (FoxO3a)/Bim signaling pathway in an isoform-specific manner, with ApoE2 and ApoE3, but not ApoE4 showing neuroprotective effects

Summary

Introduction

The apolipoprotein E gene (APOE) has three major variants, APOE2, APOE3 and APOE4; so far APOE has been confirmed as the strongest genetic risk modifier for lateonset Alzheimer’s disease (AD), with the APOE4 conferring an increased risk and the APOE2 conferring a decreased risk relative to the common APOE3 allele [1,2]. When phosphorylated by Akt, FoxO3a is associated with 14-3-3 protein in the cytosol and excluded out from the nucleus to promote cell survival, whereas reducing Akt activity results in the nuclear translocation of FoxO3a and drive multiple downstream genes expression, such as BIM, FASL (Fas ligand) and PUMA (p53 upregulated modulator of apoptosis), triggering apoptosis [13,14]. C-Jun N-terminal Kinase (JNK), a member of the oxidative stress-activated mitogen-activated protein kinase family, regulates FoxO3a activity by phosphorylation. FoxO3a has been demonstrated to be phosphorylated by JNK at the site of serine574 (Ser574) under oxidative stress condition and accumulate in the nucleus to promote downstream pro-apoptotic gene expressions, leading to cell death [17]

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