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

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.

A Neuroprotective Action of Quercetin and Apigenin through Inhibiting Aggregation of Aβ and Activation of TRKB Signaling in a Cellular Experiment

“…Of noted, quercetin showed no protective effect in their apoptotic assay. By fluorescence quenching analysis, we confirmed the binding between quercetin and extracellular domain of TRKB, and the highest binding affinity (5.3 ± 1.9 nM) echoes the highest interacting docking score (49.77) with TRKB receptor (Chiang et al, 2021). In the pharmacokinetic study in healthy volunteers, the maximum blood concentration of oral administration with quercetin at the dose of 100 mg is 7.65 μM (Graefe et al, 2001).…”

Natural Products as Modulators of Nrf2 Signaling Pathway in Neuroprotection

“…Similar results were seen with apigenin and 7,8-dihydroxyflavone (7,8-DHF). Chiang et al (2021) proposed that the activation of the Nrf2 pathway may be partly mediated by the activation of tropomyosin receptor kinase B (TRKB), a brain-derived neurotrophic factor (BDNF) receptor, which upregulates Akt activation, an activator of Nrf2, and thus decreases the mutant Tau protein aggregation [ 32 ]. Another assay in SH-SY5Y cells stressed by high glucose concentration showed that quercetin improved cell viability through an upregulation of glyoxalase 1 activity.…”

Iron dyshomeostasis and ferroptosis in Alzheimer’s disease: Molecular mechanisms of cell death and novel therapeutic drugs and targets for AD

“…This finding indicated that quercetin can be used as a potential therapeutic drug in the management of AD by regulating the α7nAChR/Nrf2/HO-1 signaling pathway. In addition, quercetin treatment can reduce tau aggregation and protected cells against tau neurotoxicity by mediating the expression of heat shock protein family B member 1 (HSPB1), NRF2, and tropomyosin-related kinase B (TRKB) (Chiang et al, 2021). Previous studies revealed that the levels of NRF2 can be upregulated by AKT serine/threonine kinase 1 (AKT), one of the downstream proteins activated by TRKB (Yoo et al, 2017).…”