title: The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.
abstract: Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers.
authors.affiliation: Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Bo-Ra
authors.initials: BR
authors.lastname: Seo
authors.affiliation: Department of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea.
authors.forename: Sook-Jeong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee University, School of Medicine, Seoul, Korea.
authors.forename: Kyung Sook
authors.initials: KS
authors.lastname: Cho
authors.affiliation: Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Yoon
authors.affiliation: Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Electronic address: jkko@amc.seoul.kr.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016466:CHO Cells; D002738:Chloroquine / Q000633:toxicity*; D007464:Clioquinol / Q000494:pharmacology*; D003412:Cricetulus; D005260:Female; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000473:pathology; D014162:Transfection; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology; D015032:Zinc / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007476:Ionophores; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D007464:Clioquinol; D002738:Chloroquine; D015032:Zinc
keywords: Alzheimer's disease; Chloroquine (CQ); Clioquinol (ClioQ); Lysosomal pH