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Article type: Research Article
Authors: Wang, Taoa; b; 1 | Wang, Chun-Yana; c; 1 | Shan, Zhong-Yanb | Teng, Wei-Pingb | Wang, Zhan-Youa; b; *
Affiliations: [a] Department of Pathophysiology, China Medical University, Shenyang, PR China | [b] Key Laboratory of Endocrine Diseases of Liaoning Province, China Medical University, Shenyang, PR China | [c] Medical Research Laboratory, Jilin Medical College, Jilin, PR China
Correspondence: [*] Correspondence to: Zhan-You Wang, Department of Pathophysiology, Key Laboratory of Endocrine Diseases of Liaoning Province, China Medical University, Shenyang 110001, PR China. Tel./Fax: +86 24 23256666 5521; E-mail: wangzy@mail.cmu.edu.cn.
Note: [1] These authors contributed equally to this work.
Abstract: Metal dyshomeostasis in the brain helps promote amyloid-β (Aβ) deposition in Alzheimer's disease (AD). Therefore, targeting the interactions between metal and Aβ is a potential therapeutic approach for AD. The metal chelator, clioquinol (CQ), is thought to reduce Aβ deposits in the AD transgenic mouse brain, and attenuate the clinical symptoms of AD patients. However, whether oral administration of CQ reduces zinc accumulation in Aβ plaques and inhibits the amyloidogenic pathway have not been properly established in AD transgenic mice. By means of autometallographic analysis, we show for the first time that both the number and size of the zinc-containing plaques were significantly reduced in the brain of amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double transgenic mice treated with CQ (30 mg/kg/day) orally for 2 months. This was accompanied by a reduction in Aβ burden in the CQ-treated mouse brain. Furthermore, CQ treatment markedly reduced the expression levels of AβPP protein, the β-site of AβPP cleaving enzyme 1 (BACE1), PS1, and the secreted β-secretase-derived fragments of AβPP (sAβPPβ). The present data indicate that CQ is able to reduce zinc accumulation in the neuritic plaques and inhibit amyloidogenic AβPP processing in the AβPP/PS1 mouse brain.
Keywords: AβPP/PS1 transgenic mouse, Alzheimer's disease, amyloid-β, amyloidogenic pathway, clioquinol, zinc
DOI: 10.3233/JAD-2011-111874
Journal: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 549-559, 2012
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