Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice
- *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; †Howard Hughes Medical Institute, Department of Biochemistry, Box 357370, University of Washington, Seattle, WA 98195; and ‡Department of Anatomy and Neuroscience, University of Texas Medical Branch, 625 Jennie Sealy Hospital, Galveston, TX 77555
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Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved March 15, 2002 (received for review January 21, 2002)
Abstract
Endogenous metals may contribute to the accumulation of amyloid plaques in Alzheimer's disease. To specifically examine the role of synaptic zinc in the plaque accumulation, Tg2576 (also called APP2576) transgenic mice (hAPP +) expressing cerebral amyloid plaque pathology were crossed with mice lacking zinc transporter 3 (ZnT3 −/−), which is required for zinc transport into synaptic vesicles. With aging, female hAPP +:ZnT3 +/+ mice manifested higher levels of synaptic zinc, insoluble amyloid β, and plaques than males; these sex differences disappeared in hAPP +:ZnT3 −/− mice. Both sexes of hAPP +:ZnT3 −/− mice had markedly reduced plaque load and less insoluble amyloid β compared with hAPP +:ZnT3 +/+ mice. Hence, of endogenous metals, synaptic zinc contributes predominantly to amyloid deposition in hAPP + mice.
Footnotes
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↵ § To whom reprint requests should be addressed. E-mail: jkko{at}www.amc.seoul.kr.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 7317.
- Abbreviations:
- AD,
- Alzheimer's disease;
- APP,
- β-amyloid precursor protein;
- hAPP,
- human APP;
- Aβ,
- amyloid β;
- ZnT3,
- zinc transporter 3;
- TFL-Zn,
- N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulfonamide
- Copyright © 2002, The National Academy of Sciences
