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VD/VDR-mediated ATG16L1 activation reduces Alzheimer’s disease-like pathology and cognitive decline

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Abstract

Background

Despite extensive global efforts, there is currently no effective remedy for Alzheimer’s disease (AD).

Objectives

This investigation aimed to examine the impact of vitamin D/vitamin D receptor (VDR)/ATG16L1 signaling on memory in AD mice, as well as the levels of autophagy and inflammation in the hippocampus.

Results

Administering cholecalciferol cholesterol emulsion (CCE), which serves as a precursor to 1,25-OH vitamin D3, through water feeding for a duration of 12 weeks demonstrated the ability to mitigate both short-term and long-term memory impairments in AD mice. CCE treatment reduced the deposition of TAU protein in the hippocampus, suppressed the phosphorylation of TAU Thr181 and 212, and significantly decreased Aβ (1–40) levels. Moreover, CCE heightened hippocampal autophagy in AD mice, upregulated the expression of ATG16L1 and LC3B, and inhibited P62 expression. In addition, CCE supplementation attenuated hippocampal inflammation in AD mice by decreasing the levels of IL1β and TNFα and restoring the TOM1/IL1R1 pathway. The Luciferase reporter assay verified that the knockdown of VDR could impede the activation of the ATG16L1 promoter by vitamin D, and ChIP analysis confirmed that VDR could bind to the ATG16L1 promoter and exert its function.

Conclusion

CCE exhibits potential in safeguarding hippocampal neurons against AD-induced harm, stimulating autophagy, and suppressing inflammation. These effects may be regulated by VD/VDR/ATG16L1 signaling.

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Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

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Acknowledgements

None.

Funding

We are very grateful to the Yichang Central People’s Hospital for its financial support for this project.

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Authors and Affiliations

  1. Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People’s Hospital, Yichang, 443003, Hubei Province, China

    Zhixiong Huang, Hefei Huang & Yanyan Wang

  2. Department of Pharmacy, The Third Affiliated Hospital, Anhui Medical University, The First People’s Hospital of Hefei, Hefei, 230061, Anhui, China

    Wei Ang

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Contributions

Zhixiong Huang contributed to the conception of the study; Zhixiong Huang, Wei Ang, Hefei Huang, Yanyan wang performed the experiment; Zhixiong Huang and Wei Ang contributed significantly to analysis and manuscript preparation; Zhixiong Huang performed the data analyses and wrote the manuscript; Wei Ang, Hefei Huang, Yanyan Wang helped perform the analysis with constructive discussions. Zhixiong Huang reviewed the manuscript.

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Correspondence to Zhixiong Huang.

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Zhixiong Huang, Wei Ang, Hefei Huang, and Yanyan Wang declare that they have no conflict of interest.

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Huang, Z., Ang, W., Huang, H. et al. VD/VDR-mediated ATG16L1 activation reduces Alzheimer’s disease-like pathology and cognitive decline. Mol. Cell. Toxicol. (2024). https://doi.org/10.1007/s13273-024-00429-7

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