Common pesticide, dichlorodiphenyltrichloroethane (DDT), increases amyloid-β levels by impairing the function of ABCA1 and IDE: Implication for Alzheimer's disease

Gongbo Li, Chaeyoung Kim, Jaekwang Kim, Hyejin Yoon, Huadong Zhou, Jungsu Kim

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)109-122
Number of pages14
JournalJournal of Alzheimer's Disease
Volume46
Issue number1
DOIs
StatePublished - May 7 2015

Keywords

  • Alzheimer's disease
  • amyloid-β
  • amyloid-β protein precursor
  • ATP-binding cassette transporter A1
  • dichlorodiphenyldichloroethylene
  • dichlorodiphenyltrichloroethane
  • insulin-degrading enzyme
  • pesticides
  • β-site AβPPcleaving enzyme1

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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