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.