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.
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“, 2003) Pesticides DDT/DDE ApoE4 gene carriers are more susceptible to diseases; DDT interacts with ApoE (ApoE4) gene to trigger the disease by increasing Aβ levels and reduces the degradation of the peptide by targeting the Aβdegrading enzyme (Richardson et al., 2014; Li et al., 2015) Paraquat (PQ) Increased Aβ level…”
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- Authors
- Li, G., Kim, C., Kim, J., Yoon, H., Zhou, H., & Kim, J.
- Affiliations
- Mayo Clinic (US)
- Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA
- Army Medical University (CN)
- Corresponding author
- Zhou, Huadong
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2015-05-07
- Volume
- 46
- Issue
- 1
- Pages
- 109-122
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W123571090
- Cited by
- 39
- References
- 76
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 1
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- DDT, pesticide exposure
- MeSH terms
- DDT, Gene Expression Regulation, Glioma, Humans, Insulysin, Mutation, Neuroblastoma, Pesticides, RNA, Messenger, Transfection, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Statistics, Nonparametric, Cell Line, Tumor, ATP Binding Cassette Transporter 1
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