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J. Biol. Chem., Vol. 279, Issue 10, 8602-8607, March 5, 2004

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Estrogen Decreases Zinc Transporter 3 Expression and Synaptic Vesicle Zinc Levels in Mouse Brain^*

Joo-Yong Lee, Jung-Hwan Kim, Seok Ho Hong, Ji Yoon Lee, Robert A. Cherny¶, Ashley I. Bush¶||, Richard D. Palmiter**, and Jae-Young Koh

From the National Creative Research Initiative Center for the Study of Central Nervous System Zinc, and Department of Neurology and Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Seoul 138-736, Korea, the ^¶Mental Health Research Institute of Victoria and Department of Pathology, University of Melbourne, Parkville, Victoria, Australia, the ^||Department of Psychiatry, Harvard Medical School and Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129-4404, and the ^**Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, Washington 98195

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) 17-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 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 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.

Received for publication, September 2, 2003 , and in revised form, December 3, 2003.

^* This study was supported by Creative Research Initiatives of the Korean Ministry of Science and Technology (to J.-Y. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: National Creative Research Initiative Center for the Study of Central Nervous System Zinc, and Department of Neurology, University of Ulsan College of Medicine, 388-1 Poongnapdong, Songpagu, Seoul 138-736, Korea. Tel.: 82-2-3010-4127; Fax: 82-2-483-5446; E-mail: jkko{at}www.amc.seoul.kr.

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