Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Neuroprotective Action of Quercetin and Apigenin through Inhibiting Aggregation of Aβ and Activation of TRKB Signaling in a Cellular Experiment

  • Ya-Jen Chiu (School of Life Science, National Taiwan Normal University) ;
  • Yu-Shan Teng (School of Life Science, National Taiwan Normal University) ;
  • Chiung-Mei Chen (Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine) ;
  • Ying-Chieh Sun (Department of Chemistry, National Taiwan Normal University) ;
  • Hsiu Mei Hsieh-Li (School of Life Science, National Taiwan Normal University) ;
  • Kuo-Hsuan Chang (Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine) ;
  • Guey-Jen Lee-Chen (School of Life Science, National Taiwan Normal University)
  • Received : 2022.10.26
  • Accepted : 2022.11.24
  • Published : 2023.05.01
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Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with progressive memory loss and the cognitive decline. AD is mainly caused by abnormal accumulation of misfolded amyloid β (Aβ), which leads to neurodegeneration via a number of possible mechanisms such as down-regulation of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TRKB) signaling pathway. 7,8-Dihydroxyflavone (7,8-DHF), a TRKB agonist, has demonstrated potential to enhance BDNF-TRKB pathway in various neurodegenerative diseases. To expand the capacity of flavones as TRKB agonists, two natural flavones quercetin and apigenin, were evaluated. With tryptophan fluorescence quenching assay, we illustrated the direct interaction between quercetin/apigenin and TRKB extracellular domain. Employing Aβ folding reporter SH-SY5Y cells, we showed that quercetin and apigenin reduced Aβ-aggregation, oxidative stress, caspase-1 and acetylcholinesterase activities, as well as improved the neurite outgrowth. Treatments with quercetin and apigenin increased TRKB Tyr516 and Tyr817 and downstream cAMP-response-element binding protein (CREB) Ser133 to activate transcription of BDNF and BCL2 apoptosis regulator (BCL2), as well as reduced the expression of pro-apoptotic BCL2 associated X protein (BAX). Knockdown of TRKB counteracted the improvement of neurite outgrowth by quercetin and apigenin. Our results demonstrate that quercetin and apigenin are to work likely as a direct agonist on TRKB for their neuroprotective action, strengthening the therapeutic potential of quercetin and apigenin in treating AD.

Keywords

Acknowledgement

We thank the Instrumentation Center of National Taiwan Normal University (MOST 107-2731-M-003-001, MD ImageXpress Micro Confocal, BIO002000) for their support and assistance in this work. We also thank the National RNAi Core Facility, Academia Sinica, for technical support. This work was supported by Ministry of Science and Technology of Taiwan (MOST; 107-2320-B-003-006, 107-2320-B-182A-020 and 107-2811-B-003-506) and Chang Gung Medical Foundation of Taiwan (CMRPG3L0042).

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