Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc levels in mouse brain.
Previous studies suggest that female sex hormones modulate synaptic zinc levels, which may influence amyloid plaque formation and Alzheimer's disease progression. We examined the effects of ovariectomy and estrogen supplement on the levels of synaptic zinc and zinc transporter protein Znt3 in the brain. Ovariectomy was performed on 5-month-old mice, and 2 weeks later, pellets containing vehicle, low (0.18 mg/pellet), or high dose (0.72 mg) 17beta-estradiol were implanted. After 4 weeks, animals were decapitated, and blood and brain were collected for analysis. Blood analysis indicated that estrogen implants altered plasma estrogen levels in a dose-dependent manner. Analysis of brain tissue showed that ovariectomy raised hippocampal synaptic vesicle zinc levels, whereas estrogen replacement lowered these zinc levels. Western blots revealed that Znt3 levels in the brain were modulated in parallel with synaptic zinc levels, whereas no change was detected in the levels of Znt3 mRNA, as determined by Northern blot and reverse transcriptase-PCR analysis. However, mRNA levels of the delta subunit of adaptor protein complex (AP)-3, which modulates the level of Znt3 levels, were altered by estrogen depletion or replacement. These data demonstrate that estrogen alters the levels of Znt3 and synaptic vesicle zinc in female mice, probably through changing AP-3 delta expression. Since synaptic zinc may play a key role in neuronal death in acute brain injury as well as in plaque formation in Alzheimer's disease, and since estrogen may be beneficial in both conditions, our results may provide new insights into the effects of estrogen on the brain.
Lee
Joo-Yong
JY
National Creative Research Initiative Center for the Study of Central Nervous System Zinc, and Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Kim
Jung-Hwan
JH
Hong
Seok Ho
SH
Lee
Ji Yoon
JY
Cherny
Robert A
RA
Bush
Ashley I
AI
Palmiter
Richard D
RD
Koh
Jae-Young
JY
D033963:Adaptor Protein Complex 3 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002352:Carrier Proteins / Q000096:biosynthesis*; D027682:Cation Transport Proteins; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D015918:Infusion Pumps, Implantable; D017136:Ion Transport / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis*; D026901:Membrane Transport Proteins; D051379:Mice; D010052:Ovariectomy; D013572:Synaptic Vesicles / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D033963:Adaptor Protein Complex 3; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D004958:Estradiol; D015032:Zinc