Journal of Food and Drug Analysis (JFDA)
【Update Date:2023-06-21】unit:
Urolithin A exhibits a neuroprotective effect against Alzheimer’s disease by inhibiting DYRK1A activity
Huang-Ju Tua,1, Chih-Jou Sub,1, Chao-Shiang Pengb, Tony Eight Lina,c, Wei-Chun Huang Fua,b,c,d,e, Kai-Cheng Hsua,b,c,d,e ,Tsong-Long Hwangg,h,i,j,* , Shiow-Lin Pana,b,c,d,e,f,*
a Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
b Ph.D. program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
c Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
d Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
e TMU Research Center of Cancer Translational Medicine, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
f TMU Research Center of Drug Discovery, Taipei Medical University, No.250, Wu-Xing Street, Xinyi Dist., Taipei 110, Taiwan
g Graduate Institute of Natural Products, College of Medicine, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist., Taoyuan City 333, Taiwan
h Research Center for Chinese Herbal Medicine, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Taoyuan City 33303, Taiwan
i Department of Anesthesiology, Chang Gung Memorial Hospital, No.259, Wenhua 1st Rd., Guishan Dist., Taoyuan City 333, Taiwan
j Department of Chemical Engineering, Ming Chi University of Technology, No.84 Gungjuan Rd., New Taipei City 243303, Taiwan
Alzheimer’s disease (AD) is a devastating neurodegenerative disease with more than 50 million people suffer from it. Unfortunately, none of the currently available drugs is able to improve cognitive impairment in AD patients. Urolithin A (UA) is a metabolite obtained from ellagic acid and ellagitannin through the intestinal flora, and it has antioxidant and anti-inflammatory properties. Previous reports found that UA had neuroprotective effects in an AD animal model, but the detailed mechanism still needs to be elucidated. In this study, we performed kinase-profiling to show that dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is the main target of UA. Studies showed that the level of DYRK1A in AD patients' brains was higher than that of healthy people, and it was closely related to the occurrence and progression of AD. Our results revealed that UA significantly reduced the activity of DYRK1A, which led to de-phosphorylation of tau and further stabilized microtubule polymerization. UA also provided neuroprotective effects by inhibiting the production of inflammatory cytokines caused by Ab. We further showed that UA significantly improved memory impairment in an AD-like mouse model. In summary, our results indicate that UA is a DYRK1A inhibitor that may provide therapeutic advantages for AD patients.
Keywords: Alzheimer's disease, DYRK1A, Tau, Urolithin A
https://doi.org/10.38212/2224-6614.3462