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 ERβagonist 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 ERβwith 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 uM)dose-dependently increased phagocytosis of o-FAM-Aβ42 in primary microglia and BV2 cells through enhancing Efβ/TLR4 signaling;PTA treatment ameliorated o-Aβ25-3s-induced reduction of synapse-related proteins VAMP2 and PSD95 in primary neurons through enhancing ERβ/BDNF/TrkB/CREB pathways;PTA treatment alleviated o-Aβ2s-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.

Qiu-ying Yan;Jian-lu Lv;Xing-yi Shen;Xing-nan Ou-Yang;Juan-zhen Yang;Rui-fang Nie;Jian Lu;Yu-jie Huang;Jia-ying Wang;Xu Shen

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy,Nanjing University of Chinese Medicine,Nanjing 210023,China

中国药理学报（英文版）

[1]Qiu-ying Yan;Jian-lu Lv;Xing-yi Shen;Xing-nan Ou-Yang;Juan-zhen Yang;Rui-fang Nie;Jian Lu;Yu-jie Huang;Jia-ying Wang;Xu Shen-.Patchouli alcohol as a selective estrogen receptor β agonist ameliorates AD-like pathology of APP/PS1 model mice)[J].中国药理学报（英文版）,2022(09):2226-2241

Patchouli,postmenpausal,patchouli,uM,VAMP2

alcohol,selective,estrogen,receptor,agonist,ameliorates,AD,pathology,PS1,model,mice,Clinical,evidence,shows,that,women,are,almost,twice,likely,develop,Alzheimer,same,age,closely,related,occurrence,Estrogen,ER,mainly,expressed,mammary,gland,other,reproductive,organs,uterus,while,largely,distributed,hippocampus,cardiovascular,system,suggesting,valuable,drug,against,neurodegenerative,diseases,low,tendency,inducing,cancers,breast,In,this,study,identified,natural,PTA,which,improved,cognitive,defects,female,explore,underlying,mechanisms,Six,month,old,were,administered,days,We,first,demonstrated,bound,dissociation,constant,KD,nM,microscale,thermophoresis,Then,showed,administration,dose,dependently,ameliorated,evaluated,Morris,water,maze,testes,Furthermore,reduced,amyloid,plaque,deposition,by,promoting,microglial,phagocytosis,synaptic,integrity,through,enhancing,BDNF,TrkB,CREB,signaling,oxidative,stress,Catalase,level,regulated,Bcl,family,proteins,therapeutic,effects,also,observed,vitro,increased,FAM,primary,BV2,cells,Ef,TLR4,treatment,3s,induced,reduction,synapse,PSD95,neurons,pathways,alleviated,2s,targeting,increasing,expression,Together,has,addressed,efficacy,amelioration,highlighted,potential,lead,compound

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