Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

被引:138
作者
Matlack, Kent E. S. [1 ]
Tardiff, Daniel F. [1 ]
Narayan, Priyanka [1 ]
Hamamichi, Shusei [2 ]
Caldwell, Kim A. [2 ]
Caldwell, Guy A. [2 ]
Lindquist, Susan [1 ,3 ,4 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA
[3] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA
[4] MIT, Dept Biol, Cambridge, MA 02142 USA
基金
美国国家卫生研究院;
关键词
phenotypic small-molecule screen; metal chelation; ALPHA-SYNUCLEIN TOXICITY; ALZHEIMERS-DISEASE; COMMON VARIANTS; PROTEIN; NEURODEGENERATION; IDENTIFICATION; AGGREGATION; TRAFFICKING; A-BETA-40; CU(II);
D O I
10.1073/pnas.1402228111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-beta peptide (A beta) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by A beta has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of A beta toxicity where the A beta peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic A beta 1-42 peptide forms more oligomers and is more toxic than A beta 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of similar to 140,000 compounds for rescue of A beta toxicity. Of similar to 30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce A beta burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of A beta secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced A beta peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent A beta oligomer formation contributes to A beta toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the A beta yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.
引用
收藏
页码:4013 / 4018
页数:6
相关论文
共 43 条
[1]   Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ [J].
Adlard, Paul A. ;
Cherny, Robert A. ;
Finkelstein, David I. ;
Gautier, Elisabeth ;
Robb, Elysia ;
Cortes, Mikhalina ;
Volitakis, Irene ;
Liu, Xiang ;
Smith, Jeffrey P. ;
Perez, Keyla ;
Laughton, Katrina ;
Li, Qiao-Xin ;
Charman, Susan A. ;
Nicolazzo, Joseph A. ;
Wilkins, Simon ;
Deleva, Karolina ;
Lynch, Toni ;
Kok, Gaik ;
Ritchie, Craig W. ;
Tanzi, Rudolph E. ;
Cappai, Roberto ;
Masters, Colin L. ;
Barnham, Kevin J. ;
Bush, Ashley I. .
NEURON, 2008, 59 (01) :43-55
[2]   Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis [J].
Atwood, CS ;
Moir, RD ;
Huang, XD ;
Scarpa, RC ;
Bacarra, NME ;
Romano, DM ;
Hartshorn, MK ;
Tanzi, RE ;
Bush, AI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) :12817-12826
[3]   Metallostasis in Alzheimer's disease [J].
Ayton, Scott ;
Lei, Peng ;
Bush, Ashley I. .
FREE RADICAL BIOLOGY AND MEDICINE, 2013, 62 :76-89
[4]   RAPID INDUCTION OF ALZHEIMER A-BETA AMYLOID FORMATION BY ZINC [J].
BUSH, AI ;
PETTINGELL, WH ;
MULTHAUP, G ;
PARADIS, MD ;
VONSATTEL, JP ;
GUSELLA, JF ;
BEYREUTHER, K ;
MASTERS, CL ;
TANZI, RE .
SCIENCE, 1994, 265 (5177) :1464-1467
[5]   Human Genetic Variation, Shared and Private [J].
Casals, Ferran ;
Bertranpetit, Jaume .
SCIENCE, 2012, 337 (6090) :39-40
[6]   Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice [J].
Cherny, RA ;
Atwood, CS ;
Xilinas, ME ;
Gray, DN ;
Jones, WD ;
McLean, CA ;
Barnham, KJ ;
Volitakis, I ;
Fraser, FW ;
Kim, YS ;
Huang, XD ;
Goldstein, LE ;
Moir, RD ;
Lim, JT ;
Beyreuther, K ;
Zheng, H ;
Tanzi, RE ;
Masters, CL ;
Bush, AI .
NEURON, 2001, 30 (03) :665-676
[7]   Identification and Rescue of α-Synuclein Toxicity in Parkinson Patient-Derived Neurons [J].
Chung, Chee Yeun ;
Khurana, Vikram ;
Auluck, Pavan K. ;
Tardiff, Daniel F. ;
Mazzulli, Joseph R. ;
Soldner, Frank ;
Baru, Valeriya ;
Lou, Yali ;
Freyzon, Yelena ;
Cho, Sukhee ;
Mungenast, Alison E. ;
Muffat, Julien ;
Mitalipova, Maisam ;
Pluth, Michael D. ;
Jui, Nathan T. ;
Schuele, Birgitt ;
Lippard, Stephen J. ;
Tsai, Li-Huei ;
Krainc, Dimitri ;
Buchwald, Stephen L. ;
Jaenisch, Rudolf ;
Lindquist, Susan .
SCIENCE, 2013, 342 (6161) :983-987
[8]   α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models [J].
Cooper, Antony A. ;
Gitler, Aaron D. ;
Cashikar, Anil ;
Haynes, Cole M. ;
Hill, Kathryn J. ;
Bhullar, Bhupinder ;
Liu, Kangning ;
Xu, Kexiang ;
Strathearn, Katherine E. ;
Liu, Fang ;
Cao, Songsong ;
Caldwell, Kim A. ;
Caldwell, Guy A. ;
Marsischky, Gerald ;
Kolodner, Richard D. ;
LaBaer, Joshua ;
Rochet, Jean-Christophe ;
Bonini, Nancy M. ;
Lindquist, Susan .
SCIENCE, 2006, 313 (5785) :324-328
[9]   Therapeutic Redistribution of Metal Ions To Treat Alzheimer's Disease [J].
Crouch, Peter J. ;
Barnham, Kevin J. .
ACCOUNTS OF CHEMICAL RESEARCH, 2012, 45 (09) :1604-1611
[10]   Coordination Features and Affinity of the Cu2+ Site in the α-Synuclein Protein of Parkinson's Disease [J].
Dudzik, Christopher G. ;
Walter, Eric D. ;
Millhauser, Glenn L. .
BIOCHEMISTRY, 2011, 50 (11) :1771-1777