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PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer’s disease mouse model by activating Nrf2 signaling pathway

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

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Fig. 1: The chemical structure of PHPB and the experimental process.
Fig. 2: Effect of PHPB on the improvement of cognitive impairment evaluated via step-down passive avoidance test.
Fig. 3: Effect of PHPB on the amelioration of oxidative injury in the brain tissue of APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 4: Effect of PHPB on the improvement of antioxidant capacity in brain tissue of APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 5: Effect of PHPB on Aβ deposition and glial activation in the brain tissue of 5-month-old APP/PS1 mice and APP/PS1-Nrf2 KO mice. The blue color represents mice of 5 months age.
Fig. 6: Effect of PHPB on Aβ deposition, GFAP and Iba1 in the brain tissue of 13-month-old APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 7: Effect of PHPB on glial activation protein levels in the brain tissue of APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 8: Effect of PHPB on the regulation of Nrf2 pathway proteins in the brain tissue of 5-month-old APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 9: Effect of PHPB on the regulation of Nrf2 pathway proteins in the brain tissue of 13-month-old APP/PS1 mice and APP/PS1-Nrf2 KO mice.
Fig. 10: Effect of PHPB on the regulation of p-AKT/AKT and p-GSK3β/GSK3β protein levels in SK-N-SH APPwt cell model.
Fig. 11: Effect of PHPB on the regulation of Nrf2 and its downstream proteins in SK-N-SH APPwt cell model.

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Acknowledgements

This project was supported by grants from the National Natural Science Foundation of China (No. 81673420 and 81872855), the CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-028) and the Disciplines Construction Project (20190200802).

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  1. These authors contributed equally: Nian-ying Shang, Long-jian Huang.

Authors and Affiliations

  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Nian-ying Shang, Long-jian Huang, Jia-qi Lan, Yu-ying Kang, Jing-shu Tang, Hong-yue Wang, Xin-nan Li, Zhuo Sun, Qiu-yu Chen, Meng-yao Liu, Zi-peng Wen, Lei Wu & Ying Peng

  2. Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China

    Xin-hong Feng

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Contributions

NYS, LJH and YP designed research; NYS, LJH, JQL, YYK, JST, HYW, XNL, ZS, QYC, MYL, ZPW, XHF and LW performed research; NYS, LJH and YP contributed new analytical tools and reagents; NYS and LJH analyzed data; NYS, LJH and YP wrote the paper.

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Correspondence to Ying Peng.

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Shang, Ny., Huang, Lj., Lan, Jq. et al. PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer’s disease mouse model by activating Nrf2 signaling pathway. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01240-9

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