title: Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AβPP/PS1 transgenic mouse brain.
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.
authors.affiliation: Department of Pathophysiology, China Medical University, Shenyang, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Zhong-Yan
authors.initials: ZY
authors.lastname: Shan
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Teng
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007464:Clioquinol / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013054:Spectrophotometry, Atomic; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D007464:Clioquinol; D015032:Zinc