Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression
Open accessAbstract
Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.
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Dysregulation of ABCA1 impairs lipidation of APOE and reduces Aβ clearance, a process exacerbated by DDT, which suppresses LXRα-mediated ABCA1 expression.
“Dysregulation of ABCA1, for example, impairs the lipidation of APOE and reduces Aβ clearance, a process exacerbated by environmental toxins such as dichlorodiphenyltrichloroethane (DDT), which suppresses liver X receptor alpha (LXRα)-mediated ABCA1 expression [36].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [36]
The Introduction says ABCA1 mediates ApoE lipidation and is critical for Aβ clearance. The Results report lower LXRα and ABCA1 protein levels and poorer Aβ clearance with DDT treatment. But the Discussion describes DDT’s disruption of ABCA1 expression *through* LXRα as a speculation, whereas the claim presents that mechanism as established. (LLM, conf=0.84)
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Cites
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370 · cited 1× · see citing works
“Cumulatively, ABCA1-mediated ApoE lipidation is thought to be necessary for the efficient clearance of Aβ and the improvement of cognitive impairment (Wahrle et al., 2008; Corona et al., 2016; Fitz et al., 2017).”
BackgroundTerwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 181 · see citing works
ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · cited 2× · see citing works
“Interestingly, dysfunctional ABCA1 contributes to the development of type 2 diabetes through increased cholesterol levels in pancreatic β-cells (Koldamova et al., 2014).”
BackgroundNuclear receptors in neurodegenerative diseases
Skerrett, R., Malm, T., & Landreth, G. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.019 · Cited by 94 · see citing works
Li, G., Kim, C., Kim, J., Yoon, H., Zhou, H., & Kim, J. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150024 · Cited by 39 · cited 3× · see citing works
“Based on our previous study (Li et al., 2015), 1 μMDDT slightly increased Aβ levels and 10 μMDDT had the most dramatic effect on Aβ levels.”
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Hein, Z. M., Karikalan, B., Gopalakrishna, P. K., Dhevi, K., Alkatiri, A., Hussan, F., Mohd Moklas, M. A., Jagadeesan, S., Che Ramli, M. D., Che Mohd Nassir, C. M. N., et al. (2026) · Molecular Neurobiology · doi:10.1007/s12035-025-05602-0 · Cited by 43 · see citing works
- Authors
- Wu, D., Hu, Y., Song, M., & Li, G.
- Affiliations
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Corresponding author
- Li, Gongbo
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2021-05-11
- Volume
- 13
- Pages
- 634948-634948
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC8144330
- OpenAlex
- W3162432672
- Cited by
- 7
- References
- 6
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission (cstc2019jcyj-msxmX0173)
- 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 › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- DDT, amyloid-beta clearance, Alzheimer's disease, liver X receptor alpha, ABCA1, environmental pollutants, organophosphorus pesticides, T0901317, neurotoxicity, astrocytes, neuroglioma cells
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