title: Common Pesticide, Dichlorodiphenyltrichloroethane (DDT), Increases Amyloid-β Levels by Impairing the Function of ABCA1 and IDE: Implication for Alzheimer's Disease.
abstract: While early-onset familial Alzheimer's disease (AD) is caused by a genetic mutation, the vast majority of late-onset AD is likely caused by the combination of genetic and environmental factors. Unlike genetic studies, potential environmental factors affecting AD pathogenesis have not yet been thoroughly investigated. Among environmental factors, pesticides seem to be one of critical environmental contributors to late-onset AD. Recent studies reported that the serum and brains of AD patients have dramatically higher levels of a metabolite of dichlorodiphenyltrichloroethane (DDT). While these epidemiological studies provided initial clues to the environmental risks potentially contributing to disease pathogenesis, a functional approach is required to determine whether they actually have a causal role in disease development. In our study, we addressed this critical knowledge gap by investigating possible mechanisms by which DDT affects amyloid-β (Aβ) levels. We treated H4-AβPPswe or H4 cells with DDT to analyze its effect on Aβ metabolism using Aβ production, clearance, and degradation assays. We found that DDT significantly increased the levels of amyloid-β protein precursor (AβPP) and β-site AβPP-cleaving enzyme1 (BACE1), affecting Aβ synthesis pathway in H4-AβPPswe cells. Additionally, DDT impaired the clearance and extracellular degradation of Aβ peptides. Most importantly, we identified for the first time that ATP-binding cassette transporter A1 (ABCA1) and insulin-degrading enzyme (IDE) are the downstream target genes adversely affected by DDT. Our findings provide insight into the molecular mechanisms by which DDT exposure may increase the risk of AD, and it further supports that ABCA1 and IDE may be potential therapeutic targets.
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.|Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Gongbo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.|Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003634:DDT / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005910:Glioma / Q000473:pathology; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010575:Pesticides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D014162:Transfection
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010575:Pesticides; D012333:RNA, Messenger; D003634:DDT; D007339:Insulysin
keywords: ATP-binding cassette transporter A1; Alzheimer’s disease; amyloid-β; amyloid-β protein precursor; dichlorodiphenyldichloroethylene; dichlorodiphenyltrichloroethane; insulin-degrading enzyme; pesticides; β-site AβPP-cleaving enzyme1