Flavones 7,8-DHF, Quercetin, and Apigenin Against Tau Toxicity via Activation of TRKB Signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells

Ni-Ni Chiang,Ying-Chieh Sun,Guey-Jen Lee-Chen,Kuo-Hsuan Chang,Hsiu Mei Hsieh-Li,Yu-Shan Teng,Te-Hsien Lin,Chiung-Mei Chen,Chung-Yin Lin,Ming-Tsan Su

doi:10.3389/fnagi.2021.758895

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

Highlights

Neurodegenerative disorders tauopathies, including the most common Alzheimer’s disease (AD), are characterized by abnormal hyperphosphorylation of microtubule-associated protein Tau that leads to the formation of neurofibrillary tangles (NFTs) and causes gain of toxic function (Iqbal et al, 2005)
We demonstrate that 7,8-DHF, quercetin, and apigenin target HSPB1, Nuclear factor erythroid 2-like 2 (NRF2), and Tropomyosin-related kinase B (TRKB) to reduce Tau aggregation and protect cells against Tau neurotoxicity, providing new treatment strategies for AD
Oxidative stress has been recognized as a contributing factor to the progression of AD and preventing oxidative stress is considered as a treatment approach for AD (Poprac et al, 2017)

Summary

Introduction

Neurodegenerative disorders tauopathies, including the most common Alzheimer’s disease (AD), are characterized by abnormal hyperphosphorylation of microtubule-associated protein Tau that leads to the formation of neurofibrillary tangles (NFTs) and causes gain of toxic function (Iqbal et al, 2005). Tau is mainly expressed in neuronal axons, where it promotes assembly and bundling of microtubules, thereby regulating vesicular transport and apoptosis (Lee et al, 2001). In retinal ganglion cells of human P301S Tau transgenic mice with early tauopathy, the impairment of tropomyosin-related kinase B (TRKB) signaling is triggered by Tau pathology and mediates the Tau-induced dysfunction of visual response (Mazzaro et al, 2016). Upon BDNF binding, TRKB phosphorylates itself and members of the mitogen-activated protein kinase (MAPK) pathway initiate intracellular signaling cascades (Levine et al, 1996). Rapid activation of extracellular signal-regulated kinase (ERK), a member of the MAPK family, by BDNF/TRKB signaling induces phosphorylation of cAMP-response element binding protein (CREB) (Bonni et al, 1999) to stimulate expression of antiapoptotic BCL2 apoptosis regulator (BCL2) (Riccio et al, 1999) for neuronal survival. As retrograde axonal transport of endosomes mediated by TRKB signaling is essential for dendrite growth of cortical neurons (Zhou et al, 2012), BDNF/TRKB potentiation would be protective in AD

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