Unveiling the neuroinflammatory potential of aspartame in Alzheimer’s disease: A comprehensive network toxicology and experimental validation approach
5 affiliations
- 1School of Nursing, Guangxi Medical University, Nanning, China
- 2Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- 3Guangxi Key Laboratory of Artificial Intelligence for Genetic Diseases of Long-dwelling Nationalities, Youjiang Medical University for Nationalities, Baise, China
- 4Institute of Life Sciences, Guangxi Medical University, Nanning, China
- 5Department of Orthopedic, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, China
Abstract
Aspartame, a widely used artificial sweetener, has raised significant concerns regarding its safety, especially in light of the rising incidence of Alzheimer’s Disease (AD). However, systematic investigations into aspartame’s potential neurotoxicity and its role in AD pathology remain limited. In this study, we employed an integrated approach combining network toxicology predictions, molecular docking, and in vitro validation to explore the neurotoxic mechanisms of aspartame in AD. By analyzing multiple public databases through network toxicology, we identified 185 common targets between aspartame and AD. Protein-protein interaction (PPI) network analysis further highlighted 10 core hub genes, including KDR, CCNE1, and GSK-3β. Molecular docking predicted favorable interactions for key targets such as GSK-3β (−5.002 kcal/mol) and KDR (−5.613 kcal/mol), with other hubs showing moderate binding affinities. In vitro experiments demonstrated that aspartame dose-dependently reduced BV2 microglial cell viability and triggered a pro-inflammatory response. Specifically, aspartame increased the production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), while upregulating the expression of GSK-3β, iNOS, TNF-α, IL-1β, and IL-6, similar to LPS-induced inflammation. These findings suggest that aspartame may induce a pro-inflammatory response in BV2 microglial cells through multiple signaling pathways, although the relevance of these findings to human neurological safety remains to be established. This study provides a basis for further investigation into the neurological safety of aspartame and proposes a novel paradigm for evaluating the neurotoxic potential of food additives using an integrated systems toxicology approach.
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BibTeX
@article{li2026unveiling,
title = {{Unveiling the neuroinflammatory potential of aspartame in Alzheimer’s disease: A comprehensive network toxicology and experimental validation approach}},
author = {Dongyang Li and Xuejun Weng and Yijuan Huang and Dongni Yang and Shunhan Yao and Weihao Zheng and Xiaohong Jiang and Yilin Wei and Sheng Xu and Chunwei Wei},
journal = {PLOS One},
year = {2026},
month = nov,
doi = {10.1371/journal.pone.0361766},
url = {https://doi.org/10.1371/journal.pone.0361766},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Unveiling the neuroinflammatory potential of aspartame in Alzheimer’s disease: A comprehensive network toxicology and experimental validation approach
AU - Dongyang Li
AU - Xuejun Weng
AU - Yijuan Huang
AU - Dongni Yang
AU - Shunhan Yao
AU - Weihao Zheng
AU - Xiaohong Jiang
AU - Yilin Wei
AU - Sheng Xu
AU - Chunwei Wei
PY - 2026
DA - 2026/11/03
JO - PLOS One
DO - 10.1371/journal.pone.0361766
UR - https://doi.org/10.1371/journal.pone.0361766
AB - Aspartame, a widely used artificial sweetener, has raised significant concerns regarding its safety, especially in light of the rising incidence of Alzheimer’s Disease (AD). However, systematic investigations into aspartame’s potential neurotoxicity and its role in AD pathology remain limited. In this study, we employed an integrated approach combining network toxicology predictions, molecular docking, and in vitro validation to explore the neurotoxic mechanisms of aspartame in AD. By analyzing multiple public databases through network toxicology, we identified 185 common targets between aspartame and AD. Protein-protein interaction (PPI) network analysis further highlighted 10 core hub genes, including KDR, CCNE1, and GSK-3β. Molecular docking predicted favorable interactions for key targets such as GSK-3β (−5.002 kcal/mol) and KDR (−5.613 kcal/mol), with other hubs showing moderate binding affinities. In vitro experiments demonstrated that aspartame dose-dependently reduced BV2 microglial cell viability and triggered a pro-inflammatory response. Specifically, aspartame increased the production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), while upregulating the expression of GSK-3β, iNOS, TNF-α, IL-1β, and IL-6, similar to LPS-induced inflammation. These findings suggest that aspartame may induce a pro-inflammatory response in BV2 microglial cells through multiple signaling pathways, although the relevance of these findings to human neurological safety remains to be established. This study provides a basis for further investigation into the neurological safety of aspartame and proposes a novel paradigm for evaluating the neurotoxic potential of food additives using an integrated systems toxicology approach.
SN - 1932-6203
ER -