Estrogen protects neuroblastoma cell from amyloid-β 42 (Aβ42)-induced apoptosis via TXNIP/TRX axis and AMPK signaling

Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-beta 42 (A beta 42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In A beta 42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued A beta 42-suppressed cell viability and protein level of TRX while inhibited A beta 42-induced increases in ROS production, cell apoptosis, Delta Psi m, and the protein levels of PERK, IRE alpha, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against A beta 42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve A beta 42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on A beta 42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.