Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.136
A Neuroprotective Action of Quercetin and Apigenin through Inhibiting Aggregation of Aβ and Activation of TRKB Signaling in a Cellular Experiment
Ya-Jen Chiu1,†, Yu-Shan Teng1,†, Chiung-Mei Chen2, Ying-Chieh Sun3, Hsiu Mei Hsieh-Li1, Kuo-Hsuan Chang2,* and Guey-Jen Lee-Chen1,*
1School of Life Science, National Taiwan Normal University, Taipei 11677,
2Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33378,
3Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
*E-mail: t43019@ntnu.edu.tw (Lee-Chen GJ), gophy5128@cgmh.org.tw (Chang KH)
Tel: +886-2-77496359 (Lee-Chen GJ), +886-3-3281200 (Chang KH)
Fax: +886-2-29312904 (Lee-Chen GJ), +886-3-3287226 (Chang KH)
†The first two authors contributed equally to this work.
Received: October 26, 2022; Revised: November 16, 2022; Accepted: November 24, 2022; Published online: January 17, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Aβ cell model, Quercetin, Apigenin, Tryptophan fluorescence quenching assay, TRKB agonists, AD therapeutics

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