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Patchouli alcohol as a selective estrogen receptor β agonist ameliorates AD-like pathology of APP/PS1 model mice

Abstract

Clinical evidence shows that postmenpausal women are almost twice as likely to develop Alzheimer’s disease (AD) as men of the same age, and estrogen is closely related to the occurrence of AD. Estrogen receptor (ER) α is mainly expressed in the mammary gland and other reproductive organs like uterus while ERβ is largely distributed in the hippocampus and cardiovascular system, suggesting that ERβ selective agonist is a valuable drug against neurodegenerative diseases with low tendency in inducing cancers of breast and other reproductive organs. In this study we identified a natural product patchouli alcohol (PTA) as a selective ERβ agonist which improved the cognitive defects in female APP/PS1 mice, and explore the underlying mechanisms. Six-month-old female APP/PS1 mice were administered PTA (20, 40 mg · kg−1 · d−1, i.g.) for 90 days. We first demonstrated that PTA bound to ERβ with a dissociation constant (KD) of 288.9 ± 35.14 nM in microscale thermophoresis. Then we showed that PTA administration dose-dependently ameliorated cognitive defects evaluated in Morris water maze and Y-maze testes. Furthermore, PTA administration reduced amyloid plaque deposition in the hippocampus by promoting microglial phagocytosis; PTA administration improved synaptic integrity through enhancing BDNF/TrkB/CREB signaling, ameliorated oxidative stress by Catalase level, and regulated Bcl-2 family proteins in the hippocampus. The therapeutic effects of PTA were also observed in vitro: PTA (5, 10, 20 μM) dose-dependently increased phagocytosis of o-FAM-Aβ42 in primary microglia and BV2 cells through enhancing ERβ/TLR4 signaling; PTA treatment ameliorated o-Aβ25-35-induced reduction of synapse-related proteins VAMP2 and PSD95 in primary neurons through enhancing ERβ/BDNF/TrkB/CREB pathways; PTA treatment alleviated o-Aβ25-35-induced oxidative stress in primary neurons through targeting ERβ and increasing Catalase expression. Together, this study has addressed the efficacy of selective ERβ agonist in the amelioration of AD and highlighted the potential of PTA as a drug lead compound against the disease.

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Fig. 1: PTA enhanced microglial phagocytosis of o-Aβ42 through ERβ/TLR4 signaling.
Fig. 2: PTA antagonized the o-Aβ25–35-induced decrease in the levels of VAMP2 and PSD95 in primary neurons.
Fig. 3: PTA antagonized o-Aβ25–35-induced suppression on ERβ/BDNF/TrkB/CREB pathway in primary neurons.
Fig. 4: PTA improved o-Aβ25–35-induced mitochondrial dysfunction and Catalase expression decrease by targeting ERβ in primary neurons.
Fig. 5: PTA improved cognitive impairment and promoted microglial phagocytosis of Aβ in the hippocampus of APP/PS1 mice.
Fig. 6: PTA improved synaptic impairment and upregulated BDNF/TrkB/CREB pathway in the hippocampus of APP/PS1 mice.
Fig. 7: PTA decreased oxidative stress and regulated Bcl-2 family proteins in the hippocampus APP/PS1 mice.
Fig. 8: Proposed mechanism for PTA in the amelioration of cognitive impairment of female APP/PS1 mice.

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Acknowledgements

This work was supported by Innovative Research Team of Six Talent Peaks Project in Jiangsu Province (TD-SWYY-013), the National Natural Science Foundation for Young Scientists of China (81703806), the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine (NZY81703806), the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine (No. 2020YLXK018), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_1737).

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QYY, JYW, and XS designed the study. QYY, JLL, XYS, XNOY, and RFN performed the research. QYY and JLL wrote the paper. JL, YJH, and JZY contributed new reagents or analytic tools. QYY analyzed data. QYY, JLL, JYW, and XS are the guarantors of this work.

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Correspondence to Jia-ying Wang or Xu Shen.

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The authors declare no competing interests.

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Yan, Qy., Lv, Jl., Shen, Xy. et al. Patchouli alcohol as a selective estrogen receptor β agonist ameliorates AD-like pathology of APP/PS1 model mice. Acta Pharmacol Sin 43, 2226–2241 (2022). https://doi.org/10.1038/s41401-021-00857-4

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  • DOI: https://doi.org/10.1038/s41401-021-00857-4

Keywords

  • Alzheimer’s disease
  • patchouli alcohol
  • amyloid-β
  • ER selective agonist
  • Toll-like receptor 4
  • synaptic plasticity

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