Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake.
Dysregulation of iron homeostasis is involved in the pathological process of Alzheimer's disease (AD). We have recently reported that divalent metal transporter 1 (DMT1) is upregulated in an AD transgenic mouse brain, and that silencing of DMT1, which reduces cellular iron influx, results in inhibition of amyloidogenesis in vitro, suggesting a potential target of DMT1 for AD therapy. In the present study, we tested the hypothesis that inhibition of DMT1 with ebselen, a DMT1 transport inhibitor, could affect tau phosphorylation. Human neuroblastoma SH-SY5Y cells were pre-treated with ebselen and then treated with ferrous sulfate (dissolved in ascorbic acid), and the effects of ebselen on tau phosphorylation and the relative signaling pathways were examined. Our results showed that ebselen decreased iron influx, reduced iron-induced ROS production, inhibited the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3β, and ultimately attenuated the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. The present study indicates that the neuroprotective effect of ebselen on AD is not only related to its antioxidant activity as reported previously, but is also associated with a reduction in tau phosphorylation by inhibition of DMT1.
Department of Pathophysiology, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang 110001, PR China.
Ling
L
Xie
Wei
W
Zheng
Na
N
Xin
Jing-Wei
JW
Xie
Tao
T
Wang
Zhan-You
ZY
Wang
D001393:Azoles / Q000494:pharmacology*; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007501:Iron / Q000378:metabolism*; D054833:Isoindoles; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism*; D000099236:Solute Carrier Family 11, Member 2
D001393:Azoles; D027682:Cation Transport Proteins; D007501:Iron; D054833:Isoindoles; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D016875:tau Proteins; D000099236:Solute Carrier Family 11, Member 2; C042986:ebselen