image: (A) Western blot analysis of ATOX1 protein levels in the cortical and hippocampal samples from 5-month-old C57BJ/L mice. (B) Western blot analysis of ATOX1 protein levels in the hippocampal samples from 5-month-old wild-type and 5 × FAD mice. (C) Quantifications of ATOX1 protein levels. (D) The mRNA levels of ATOX1 in wild-type and 5 × FAD mice were detected by real-time PCR. ∗∗p < 0.01; t-test and Tukey's post hoc analysis. (E) Quantifications of ATOX1 mRNA levels in neurons, astrocytes, and microglia. (F) The ATOX1 protein levels in neurons, astrocytes, and microglia were detected by Western blot analysis. (G) Quantifications of ATOX1 protein levels. ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001; data were reported as mean ± standard error of the mean; one-way ANOVA with Tukey's post hoc analysis.
Credit: Fuxin Zhong, Jiani Wu, Zhangjing Deng, Wuhan Yu, Jiaqi Song, Yingxi Chen, Weihua Yu, Yang Lü
Alzheimer's disease (AD) is a devastating neurodegenerative disorder heavily characterized by amyloid-beta (Aβ) plaques, progressive cognitive decline, and profound neuroinflammation. While copper (Cu2+) accumulation near Aβ plaques is a known driver of oxidative stress and microglial dysfunction, the precise molecular mechanisms regulating microglial copper homeostasis have largely remained unexplored.
This new research, published in the Genes & Diseases journal by a team from Chongqing Medical University, investigated the critical protective role of Antioxidant protein 1 (ATOX1) in mitigating copper-induced neurotoxicity and inflammation in AD.
Through comprehensive in vivo analyses using a 5 × FAD mouse model and in vitro Aβ1-42-treated microglial models, the researchers discovered a profound dysregulation of copper transport. The data revealed that ATOX1 expression is significantly downregulated in microglia specifically associated with Aβ-plaques, strongly correlating with severe intracellular copper accumulation. Extensive molecular and co-immunoprecipitation assays deciphered the underlying intracellular mechanism, demonstrating that ATOX1 normally acts as an essential copper chaperone. ATOX1 directly interacts with the copper exporter ATP7B, facilitating the transfer and subsequent efflux of excess Cu2+ out of the cell. In the AD model, the stark deficiency of ATOX1 disrupts this vital transport chain, leading to a massive intracellular accumulation of copper. This metal overload aggressively induces cellular oxidative stress, evidenced by depleted glutathione (GSH) levels, elevated lipid peroxidation (MDA), and decreased superoxide dismutase (SOD) activity.
Remarkably, in vitro models confirmed that lentiviral-mediated overexpression of ATOX1 successfully cleared the intracellular copper overload and rescued the microglia from Aβ-induced neurotoxicity. By restoring the ATOX1-ATP7B signaling axis, the engineered microglia exhibited profoundly enhanced antioxidant capacity. Furthermore, ATOX1 overexpression drastically reduced the expression of pro-apoptotic proteins like Bax and cleaved caspase-3, restored anti-apoptotic Bcl2 levels, and significantly diminished the secretion of core pro-inflammatory cytokines, including IL-1β and IL-6.
While these collective data robustly highlight the critical influence of tightly regulated metal homeostasis on microglial survival and functionality, additional clinical studies are necessary to translate these findings into human applications.
In conclusion, targeting the ATOX1-ATP7B copper transport axis offers a powerful new strategy to shield microglia from oxidative stress and halt neuroinflammation. This profound finding positions ATOX1 upregulation and targeted copper modulation as compelling therapeutic strategies for the next generation of Alzheimer's disease treatments.
Reference
Title of Original Paper: ATOX1 overexpression mitigates copper homeostasis in microglia: Implications for Alzheimer's disease therapy
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101888
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