{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T14:02:42Z","timestamp":1793887362051,"version":"4.8.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"\u00d6sterreichischen Akademie der Wissenschaften","award":["24838"],"award-info":[{"award-number":["24838"]}]},{"name":"Wiener Wissenschafts-und Technologie-Fonds WWTF LS17-026"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neurodegenerative disorders (ND) like Alzheimer\u2019s (AD), Parkinson\u2019s (PD), Huntington\u2019s or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the \u2018metal hypothesis of Alzheimer\u2019s disease\u2019 that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid \u00df (A\u00df) expressing <jats:italic>Caenorhabditis elegans,<\/jats:italic> whereas it is not in wild type strains. Further MT induction collapsed in 8\u00a0days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO<jats:sub>4<\/jats:sub>, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of A\u00df and \u03b1-synuclein toxicity in transgenic <jats:italic>C. elegans<\/jats:italic> models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.<\/jats:p>","DOI":"10.1038\/s41598-020-68561-7","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T10:02:53Z","timestamp":1594893773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Prolongation of metallothionein induction combats A\u00df and \u03b1-synuclein toxicity in aged transgenic Caenorhabditis elegans"],"prefix":"10.1038","volume":"10","author":[{"given":"Dagmar","family":"Pretsch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith Maria","family":"Rollinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-4387","authenticated-orcid":false,"given":"Miroslav","family":"Genov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"W\u00f6hrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liselotte","family":"Krenn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Moloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameya","family":"Kasture","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Pretsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"issue":"5580","key":"68561_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer\u2019s disease: progress and problems on the road to therapeutics. Science 297(5580), 353\u2013356. https:\/\/doi.org\/10.1126\/science.1072994 (2002).","journal-title":"Science"},{"issue":"8","key":"68561_CR2","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1093\/jnen\/60.8.759","volume":"60","author":"A Nunomura","year":"2001","unstructured":"Nunomura, A. et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60(8), 759\u2013767. https:\/\/doi.org\/10.1093\/jnen\/60.8.759 (2001).","journal-title":"J. Neuropathol. Exp. Neurol."},{"issue":"43","key":"68561_CR3","doi-asserted-by":"publisher","first-page":"40302","DOI":"10.1074\/jbc.M206428200","volume":"277","author":"C Opazo","year":"2002","unstructured":"Opazo, C. et al. Metalloenzyme-like activity of Alzheimer\u2019s disease \u00df-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological reducing agents to neurotoxic H2O2. J. Biol. Chem. 277(43), 40302\u201340308. https:\/\/doi.org\/10.1074\/jbc.M206428200 (2002).","journal-title":"J. Biol. Chem."},{"key":"68561_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19082449","author":"Y Sadakane","year":"2018","unstructured":"Sadakane, Y. & Kawahara, M. Implications of metal binding and asparagine deamidation for amyloid formation. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms19082449 (2018).","journal-title":"Int. J. Mol. Sci."},{"issue":"3","key":"68561_CR5","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.nurt.2008.05.001","volume":"5","author":"AI Bush","year":"2008","unstructured":"Bush, A. I. & Tanzi, R. E. Therapeutics for Alzheimer\u2019s disease based on the metal hypothesis. Neurotherapeutics 5(3), 421\u2013432. https:\/\/doi.org\/10.1016\/j.nurt.2008.05.001 (2008).","journal-title":"Neurotherapeutics"},{"key":"68561_CR6","doi-asserted-by":"publisher","first-page":"6727","DOI":"10.1039\/c4cs00138a","volume":"43","author":"KJ Barnham","year":"2014","unstructured":"Barnham, K. J. & Bush, A. I. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem. Soc. Rev. 43, 6727\u20136749. https:\/\/doi.org\/10.1039\/c4cs00138a (2014).","journal-title":"Chem. Soc. Rev."},{"issue":"11","key":"68561_CR7","doi-asserted-by":"publisher","first-page":"975","DOI":"10.18632\/aging.100689","volume":"6","author":"IM Klang","year":"2014","unstructured":"Klang, I. M. et al. Iron promotes protein insolubility and aging in C. elegans. Aging 6(11), 975\u2013988. https:\/\/doi.org\/10.18632\/aging.100689 (2014).","journal-title":"Aging"},{"issue":"2","key":"68561_CR8","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s10534-017-0005-2","volume":"30","author":"F Tahmsebinia","year":"2017","unstructured":"Tahmsebinia, F. & Emadi, S. Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron. Biometals 30(2), 285\u2013293. https:\/\/doi.org\/10.1007\/s10534-017-0005-2 (2017).","journal-title":"Biometals"},{"issue":"3","key":"68561_CR9","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/s0896-6273(01)00317-8","volume":"30","author":"RA Cherny","year":"2001","unstructured":"Cherny, R. A. et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits \u03b2-amyloid accumulation in Alzheimer\u2019s disease transgenic mice. Neuron 30(3), 665\u2013676. https:\/\/doi.org\/10.1016\/s0896-6273(01)00317-8 (2001).","journal-title":"Neuron"},{"key":"68561_CR10","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.freeradbiomed.2012.10.558","volume":"62","author":"S Ayton","year":"2013","unstructured":"Ayton, S., Lei, P. & Bush, A. I. Metallostasis in Alzheimer\u2019s disease. Free Radic. Biol. Med. 62, 76\u201389. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2012.10.558 (2013).","journal-title":"Free Radic. Biol. Med."},{"key":"68561_CR11","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.3233\/JAD-170662","volume":"62","author":"PA Adlard","year":"2018","unstructured":"Adlard, P. A. & Bush, A. I. Metals and Alzheimer\u2019s disease: How far have we come in the clinic?. J. Alzheimers Dis. 62, 1369\u20131379. https:\/\/doi.org\/10.3233\/JAD-170662 (2018).","journal-title":"J. Alzheimers Dis."},{"key":"68561_CR12","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1111\/j.1742-4658.2010.07667.x","volume":"277","author":"S Zeitoun-Ghandour","year":"2010","unstructured":"Zeitoun-Ghandour, S. et al. The two Caenorhabditis elegans metallothioneins (CeMT-1 and CeMT-2) discriminate between essential zinc and toxic cadmium. FEBS J. 277, 2531\u20132542. https:\/\/doi.org\/10.1111\/j.1742-4658.2010.07667.x (2010).","journal-title":"FEBS J."},{"key":"68561_CR13","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s00018-002-8454-2","volume":"59","author":"P Coyle","year":"2002","unstructured":"Coyle, P., Philcox, J. C., Carey, L. C. & Rofe, A. M. Metallothionein: The multipurpose protein. Cell. Mol. Life Sci. CMLS 59, 627\u2013647. https:\/\/doi.org\/10.1007\/s00018-002-8454-2 (2002).","journal-title":"Cell. Mol. Life Sci. CMLS"},{"issue":"1","key":"68561_CR14","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.arr.2010.09.007","volume":"10","author":"WR Swindell","year":"2011","unstructured":"Swindell, W. R. Metallothionein and the biology of aging. Ageing Res. Rev. 10(1), 132\u2013145. https:\/\/doi.org\/10.1016\/j.arr.2010.09.007 (2011).","journal-title":"Ageing Res. Rev."},{"issue":"8","key":"68561_CR15","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1021\/bi201774z","volume":"51","author":"JT Pedersen","year":"2012","unstructured":"Pedersen, J. T. et al. Rapid exchange of metal between Zn (7)-metallothionein-3 and amyloid-beta peptide promotes amyloid-related structural changes. Biochemistry 51(8), 1697\u20131706. https:\/\/doi.org\/10.1021\/bi201774z (2012).","journal-title":"Biochemistry"},{"issue":"9","key":"68561_CR16","first-page":"129","volume":"2","author":"P Zhang","year":"2013","unstructured":"Zhang, P. et al. Effects of metallothionein on nervous system and neurological diseases. Int. J. Biol. Biol. Sci. 2(9), 129\u2013135 (2013).","journal-title":"Int. J. Biol. Biol. Sci."},{"key":"68561_CR17","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1248\/bpb.b17-00856","volume":"41","author":"S Nakamura","year":"2018","unstructured":"Nakamura, S., Shimazawa, M. & Hara, H. Physiological roles of metallothioneins in central nervous system diseases. Biol. Pharm. Bull. 41, 1006\u20131013. https:\/\/doi.org\/10.1248\/bpb.b17-00856 (2018).","journal-title":"Biol. Pharm. Bull."},{"key":"68561_CR18","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5828056","author":"D Juarez-Rebollar","year":"2017","unstructured":"Juarez-Rebollar, D., Rios, C., Nava-Ruiz, C. & Mendez-Armenta, M. Metallothionein in brain disorders. Oxid. Med. Cell. Long. https:\/\/doi.org\/10.1155\/2017\/5828056 (2017).","journal-title":"Oxid. Med. Cell. Long."},{"key":"68561_CR19","doi-asserted-by":"publisher","first-page":"510","DOI":"10.3389\/fnins.2018.00510","volume":"12","author":"R Sirabella","year":"2018","unstructured":"Sirabella, R. et al. Ionic homeostasis maintenance in ALS: Focus on new therapeutic targets. Front. Neurosci. 12, 510. https:\/\/doi.org\/10.3389\/fnins.2018.00510 (2018).","journal-title":"Front. Neurosci."},{"issue":"1","key":"68561_CR20","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0006-8993(00)03196-6","volume":"894","author":"WH Yu","year":"2001","unstructured":"Yu, W. H. et al. Metallothionein 3 is reduced in Alzheimer\u2019s disease. Brain Res. 894(1), 37\u201345. https:\/\/doi.org\/10.1016\/S0006-8993(00)03196-6 (2001).","journal-title":"Brain Res."},{"key":"68561_CR21","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s11010-006-2390-7","volume":"283","author":"BL Martin","year":"2006","unstructured":"Martin, B. L. et al. Metallothionein-3 and neuronal nitric oxide synthase levels in brains from the Tg2576 mouse model of Alzheimer\u2019s disease. Mol. Cell. Biochem. 283, 129\u2013137. https:\/\/doi.org\/10.1007\/s11010-006-2390-7 (2006).","journal-title":"Mol. Cell. Biochem."},{"issue":"5","key":"68561_CR22","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1093\/hmg\/ddt517","volume":"23","author":"E Tokuda","year":"2014","unstructured":"Tokuda, E., Okawa, E., Watanabe, S. & Ono, S. Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1. Hum. Mol. Genet. 23(5), 1271\u20131285. https:\/\/doi.org\/10.1093\/hmg\/ddt517 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"68561_CR23","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.neuroscience.2011.05.034","volume":"189","author":"K Hashimoto","year":"2011","unstructured":"Hashimoto, K. et al. Metallothionein-III prevents neuronal death and prolongs life span in amyotrophic lateral sclerosis model mice. Neuroscience 189, 293\u2013298. https:\/\/doi.org\/10.1016\/j.neuroscience.2011.05.034 (2011).","journal-title":"Neuroscience"},{"issue":"8","key":"68561_CR24","doi-asserted-by":"publisher","first-page":"e12030","DOI":"10.1371\/journal.pone.0012030","volume":"5","author":"RS Chung","year":"2010","unstructured":"Chung, R. S. et al. The native copper- and zinc-binding protein metallothionein blocks copper-mediated A\u00df aggregation and toxicity in rat cortical neurons. PLoS ONE 5(8), e12030. https:\/\/doi.org\/10.1371\/journal.pone.0012030 (2010).","journal-title":"PLoS ONE"},{"key":"68561_CR25","doi-asserted-by":"publisher","first-page":"13763","DOI":"10.1038\/s41598-017-12800-x","volume":"7","author":"W Xu","year":"2017","unstructured":"Xu, W., Xu, Q., Cheng, H. & Tan, X. The efficacy and pharmacological mechanism of Zn7MT3 to protect against Alzheimer\u2019s disease. Sci. Rep. 7, 13763. https:\/\/doi.org\/10.1038\/s41598-017-12800-x (2017).","journal-title":"Sci. Rep."},{"issue":"3","key":"68561_CR26","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1042\/BJ20031677","volume":"380","author":"BI Yongyi","year":"2004","unstructured":"Yongyi, B. I. et al. Induction of metallothionein 1 by phenolic antioxidants requires metal-activated transcription factor 1 (MTF-1) and zinc. Biochem. J. 380(3), 695\u2013703. https:\/\/doi.org\/10.1042\/BJ20031677 (2004).","journal-title":"Biochem. J."},{"issue":"2","key":"68561_CR27","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/s12640-017-9825-7","volume":"33","author":"F McLeary","year":"2017","unstructured":"McLeary, F. et al. Dexamethasone inhibits copper-induced alpha-synuclein aggregation by a metallothionein-dependent mechanism. Neurotox. Res. 33(2), 229\u2013238. https:\/\/doi.org\/10.1007\/s12640-017-9825-7 (2017).","journal-title":"Neurotox. Res."},{"key":"68561_CR28","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S0304-3940(00)01488-9","volume":"293","author":"I Miyazaki","year":"2000","unstructured":"Miyazaki, I. et al. Expression of metallothionein-III mRNA and its regulation by levodopa in the basal ganglia of hemiparkinsonian rats. Neurosci. Lett. 293, 65\u201368 (2000).","journal-title":"Neurosci. Lett."},{"issue":"4","key":"68561_CR29","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1248\/jhs.50.323","volume":"50","author":"I Hozumi","year":"2004","unstructured":"Hozumi, I., Asanuma, M., Yamada, M. & Uchida, Y. Metallothioneins and neurodegenerative diseases. J. Health Sci. 50(4), 323\u2013331. https:\/\/doi.org\/10.1248\/jhs.50.323 (2004).","journal-title":"J. Health Sci."},{"issue":"5","key":"68561_CR30","doi-asserted-by":"publisher","first-page":"E636","DOI":"10.3390\/ijms17050636","volume":"17","author":"E Tokuda","year":"2016","unstructured":"Tokuda, E. & Furukawa, Y. Copper homeostasis as a therapeutic target in amyotrophic lateral sclerosis with SOD1 mutations. Int. J. Mol. Sci. 17(5), E636. https:\/\/doi.org\/10.3390\/ijms17050636 (2016).","journal-title":"Int. J. Mol. Sci."},{"key":"68561_CR31","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/d41586-018-05722-9","volume":"559","author":"A King","year":"2018","unstructured":"King, A. The search for better animal models of Alzheimer\u2019s disease. Nature 559, 13\u201315. https:\/\/doi.org\/10.1038\/d41586-018-05722-9 (2018).","journal-title":"Nature"},{"issue":"2","key":"68561_CR32","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1093\/toxsci\/kfp161","volume":"111","author":"G Jiang","year":"2009","unstructured":"Jiang, G. et al. Caenorhabditis elegans metallothioneins protect against toxicity induced by depleted uranium. Toxicol. Sci. 111(2), 345\u2013354. https:\/\/doi.org\/10.1093\/toxsci\/kfp161 (2009).","journal-title":"Toxicol. Sci."},{"key":"68561_CR33","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13065-015-0143-y","volume":"9","author":"X Chen","year":"2015","unstructured":"Chen, X., Barclay, J. W., Burgoyne, R. D. & Morgan, A. Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. Chem. Cent. J. 9, 65. https:\/\/doi.org\/10.1186\/s13065-015-0143-y (2015).","journal-title":"Chem. Cent. J."},{"issue":"2","key":"68561_CR34","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1534\/genetics.115.175851","volume":"200","author":"RL Gomez-Amaro","year":"2015","unstructured":"Gomez-Amaro, R. L. et al. Measuring food intake and nutrient absorption in Caenorhabditis elegans. Genetics 200(2), 443\u2013454 (2015).","journal-title":"Genetics"},{"key":"68561_CR35","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/S0140-6736(81)90062-3","volume":"1","author":"FM Burnet","year":"1981","unstructured":"Burnet, F. M. A possible role of zinc in the pathology of dementia. Lancet 1, 186\u2013188 (1981).","journal-title":"Lancet"},{"key":"68561_CR36","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1097\/00002093-199100510-00004","volume":"5","author":"J Constantinidis","year":"1991","unstructured":"Constantinidis, J. Hypothesis regarding amyloid and zinc in the pathogenesis of Alzheimer disease: Potential for preventive intervention. Alzheimer Dis. Assoc. Disord. 5, 31\u201335 (1991).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"issue":"4","key":"68561_CR37","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1248\/bpb.b12-00962","volume":"36","author":"H Hara","year":"2013","unstructured":"Hara, H., Maeda, A., Kamiya, T. & Adachi, T. Protective effects of apomorphine against zinc-induced neurotoxicity in cultured cortical neurons. Biol. Pharm. Bull. 36(4), 585\u2013591. https:\/\/doi.org\/10.1248\/bpb.b12-00962 (2013).","journal-title":"Biol. Pharm. Bull."},{"key":"68561_CR38","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1006\/bbrc.2000.2732","volume":"272","author":"M Ohta","year":"2000","unstructured":"Ohta, M. et al. Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes. Biochem. Biophys. Res. Commun. 272, 18\u201322. https:\/\/doi.org\/10.1006\/bbrc.2000.2732 (2000).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"68561_CR39","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/ana.22319","volume":"69","author":"E Himeno","year":"2011","unstructured":"Himeno, E. et al. Apomorphine treatment in Alzheimer mice promoting amyloid-\u00df degradation. Ann. Neurol. 69, 248\u2013256. https:\/\/doi.org\/10.1002\/ana.22319 (2011).","journal-title":"Ann. Neurol."},{"issue":"6","key":"68561_CR40","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1210\/mend-2-6-485","volume":"2","author":"EP Slater","year":"1988","unstructured":"Slater, E. P. et al. Progesterone induction of metallothionein-II gene expression. Mol. Endocrinol. 2(6), 485\u2013491. https:\/\/doi.org\/10.1210\/mend-2-6-485 (1988).","journal-title":"Mol. Endocrinol."},{"issue":"6","key":"68561_CR41","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.nbt.2011.05.003","volume":"28","author":"CJ Weng","year":"2011","unstructured":"Weng, C. J., Chen, M. J., Yeh, C. T. & Yen, G. C. Hepatoprotection of quercetin against oxidative stress by induction of metallothionein expression through activating MAPK and PI3K pathways and enhancing Nrf2 DNA-binding activity. New Biotechnol. 28(6), 767\u2013777. https:\/\/doi.org\/10.1016\/j.nbt.2011.05.003 (2011).","journal-title":"New Biotechnol."},{"issue":"2","key":"68561_CR42","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.cbpb.2007.10.004","volume":"149","author":"A Kampk\u00f6tter","year":"2008","unstructured":"Kampk\u00f6tter, A. et al. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp. Biochem. Physiol. Part B Biochem. Mol. Biol. 149(2), 314\u2013323. https:\/\/doi.org\/10.1016\/j.cbpb.2007.10.004 (2008).","journal-title":"Comp. Biochem. Physiol. Part B Biochem. Mol. Biol."},{"key":"68561_CR43","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.neuropharm.2015.01.027","volume":"93","author":"AM Sabogal-Gu\u00e1queta","year":"2015","unstructured":"Sabogal-Gu\u00e1queta, A. M. et al. The flavonoid quercetin ameliorates Alzheimer\u2019s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer\u2019s disease model mice. Neuropharmacology 93, 134\u2013145. https:\/\/doi.org\/10.1016\/j.neuropharm.2015.01.027 (2015).","journal-title":"Neuropharmacology"},{"issue":"7342","key":"68561_CR44","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/nature09873","volume":"427","author":"S Alavez","year":"2011","unstructured":"Alavez, S. et al. Amyloid-binding compounds maintain protein homeostasis during aging and extend lifespan. Nature 427(7342), 226\u2013229. https:\/\/doi.org\/10.1038\/nature09873 (2011).","journal-title":"Nature"},{"issue":"5","key":"68561_CR45","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s10522-008-9199-6","volume":"10","author":"K Pietsch","year":"2008","unstructured":"Pietsch, K. et al. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology 10(5), 565\u2013578. https:\/\/doi.org\/10.1007\/s10522-008-9199-6 (2008).","journal-title":"Biogerontology"},{"key":"68561_CR46","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0966com","author":"D Barsyte","year":"2001","unstructured":"Barsyte, D., Lovejoy, D. A. & Lithgow, G. J. Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. FASEB J. https:\/\/doi.org\/10.1096\/fj.99-0966com (2001).","journal-title":"FASEB J."},{"issue":"9","key":"68561_CR47","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2174\/156720501209151019105647","volume":"12","author":"S Sarkar","year":"2015","unstructured":"Sarkar, S. et al. Oral Administration of thioflavin T prevents beta amyloid plaque formation in double transgenic AD mice. Curr. Alzheimer Res. 12(9), 837\u2013846 (2015).","journal-title":"Curr. Alzheimer Res."},{"issue":"9","key":"68561_CR48","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/S1474-4422(08)70167-4","volume":"7","author":"L Lannfelt","year":"2008","unstructured":"Lannfelt, L. Safety, efficacy, and biomarker findings of PBT2 in targeting A\u00df as a modifying therapy for Alzheimer\u2019s disease: A phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 7(9), 779\u2013786. https:\/\/doi.org\/10.1016\/S1474-4422(08)70167-4 (2008).","journal-title":"Lancet Neurol."},{"issue":"33","key":"68561_CR49","doi-asserted-by":"publisher","first-page":"11840","DOI":"10.1073\/pnas.0502177102","volume":"102","author":"T Nguyen","year":"2005","unstructured":"Nguyen, T., Hamby, A. & Massa, S. M. Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington\u2019s disease mouse model. Proc. Natl. Acad. Sci. U. S. A. 102(33), 11840\u201311845. https:\/\/doi.org\/10.1073\/pnas.0502177102 (2005).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"2","key":"68561_CR50","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3233\/JHD-120029","volume":"1","author":"RA Cherny","year":"2012","unstructured":"Cherny, R. A. et al. PBT2 reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6\/2 mouse model of Huntington\u2019s disease. J. Huntingtons Dis. 1(2), 211\u2013219. https:\/\/doi.org\/10.3233\/JHD-120029 (2012).","journal-title":"J. Huntingtons Dis."},{"issue":"12","key":"68561_CR51","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1001\/archneur.60.12.1685","volume":"60","author":"CW Ritchie","year":"2003","unstructured":"Ritchie, C. W. et al. Metal-protein attenuation with iodochlorhydroxyquin (Clioquinol) targeting A\u03b2 amyloid deposition and toxicity in Alzheimer DiseaseA pilot phase 2 clinical trial. Arch. Neurol. 60(12), 1685\u20131691. https:\/\/doi.org\/10.1001\/archneur.60.12.1685 (2003).","journal-title":"Arch. Neurol."},{"issue":"1","key":"68561_CR52","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/ijnp\/pyy090","volume":"22","author":"P Zeng","year":"2019","unstructured":"Zeng, P. et al. Emodin rescued hyperhomocysteinemia-induced dementia and Alzheimer\u2019s disease-like features in rats. Int. J. Neuropsychopharmacol. 22(1), 57\u201370. https:\/\/doi.org\/10.1093\/ijnp\/pyy090 (2019).","journal-title":"Int. J. Neuropsychopharmacol."},{"issue":"2","key":"68561_CR53","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1089\/jop.2006.0118","volume":"23","author":"HJ Lin","year":"2007","unstructured":"Lin, H. J. et al. Aloe-emodin metabolites protected N-methyl-d-aspartate-treated retinal ganglion cells by Cu\u2013Zn superoxide dismutase. J. Ocul. Pharmacol. Ther. 23(2), 152\u2013171. https:\/\/doi.org\/10.1089\/jop.2006.0118 (2007).","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"68561_CR54","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20182378","author":"W Liu","year":"2019","unstructured":"Liu, W. et al. Emodin inhibits zinc-induced neurotoxicity in neuroblastoma SH-SY5Y cells. Biosci. Rep. https:\/\/doi.org\/10.1042\/BSR20182378 (2019).","journal-title":"Biosci. Rep."},{"key":"68561_CR55","doi-asserted-by":"publisher","first-page":"e451","DOI":"10.1038\/cddis.2012.187","volume":"4","author":"TC Jackson","year":"2013","unstructured":"Jackson, T. C., Verrier, J. D. & Kochanek, P. M. Anthraquinone-2-sulfonic acid (AQ2S) is a novel neurotherapeutic agent. Cell Death Dis. 4, e451. https:\/\/doi.org\/10.1038\/cddis.2012.187 (2013).","journal-title":"Cell Death Dis."},{"key":"68561_CR56","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.biopha.2018.08.037","volume":"107","author":"R Keowkase","year":"2018","unstructured":"Keowkase, R. et al. Sesamin and sesamolin reduce amyloid-\u03b2 toxicity in a transgenic Caenorhabditis elegans. Biomed. Pharmacother. 107, 656\u2013664. https:\/\/doi.org\/10.1016\/j.biopha.2018.08.037 (2018).","journal-title":"Biomed. Pharmacother."},{"key":"68561_CR57","doi-asserted-by":"publisher","unstructured":"Stiernagle, T. Maintenance of C. elegans. WormBook, ed. The C. elegans Research Community. https:\/\/doi.org\/10.1895\/wormbook.1.101.1 (2006).","DOI":"10.1895\/wormbook.1.101.1"},{"issue":"1","key":"68561_CR58","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","volume":"77","author":"S Brenner","year":"1974","unstructured":"Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77(1), 71\u201394 (1974).","journal-title":"Genetics"},{"key":"68561_CR59","doi-asserted-by":"publisher","DOI":"10.3791\/2496","author":"GM Solis","year":"2011","unstructured":"Solis, G. M. & Petraschek, M. Measuring Caenorhabditis elegans life span in 96 well microtiter plates. J. Vis. Exp. https:\/\/doi.org\/10.3791\/2496 (2011).","journal-title":"J. Vis. Exp."},{"issue":"51","key":"68561_CR60","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.3791\/2745","volume":"19","author":"CK Leung","year":"2011","unstructured":"Leung, C. K., Deonarine, A., Strange, K. & Choe, K. P. High-throughput screening and biosensing with fluorescent C. elegans strains. J. Vis. Exp. 19(51), 2745. https:\/\/doi.org\/10.3791\/2745 (2011).","journal-title":"J. Vis. Exp."},{"issue":"1","key":"68561_CR61","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1093\/geronj\/34.1.28","volume":"34","author":"D Mitchell","year":"1979","unstructured":"Mitchell, D., Stiles, W., Santelli, J. & Sanadi, D. R. Synchronous growth and aging of Caenorhabditis elegans in the presence of fluorodeoxyuridine. J. Gerontol. 34(1), 28\u201336. https:\/\/doi.org\/10.1093\/geronj\/34.1.28 (1979).","journal-title":"J. Gerontol."},{"issue":"3","key":"68561_CR62","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/s0197-4580(02)00224-5","volume":"24","author":"CD Link","year":"2003","unstructured":"Link, C. D. et al. Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer\u2019s disease model. Neurobiol. Aging 24(3), 397\u2013413. https:\/\/doi.org\/10.1016\/s0197-4580(02)00224-5 (2003).","journal-title":"Neurobiol. Aging"},{"issue":"22","key":"68561_CR63","doi-asserted-by":"publisher","first-page":"3006","DOI":"10.1101\/qad.1575307","volume":"21","author":"SM Garcia","year":"2007","unstructured":"Garcia, S. M. et al. Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post synaptic muscle cells. Genes Dev. 21(22), 3006\u20133016. https:\/\/doi.org\/10.1101\/qad.1575307 (2007).","journal-title":"Genes Dev."},{"issue":"3","key":"68561_CR64","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1534\/genetics.110.120436","volume":"186","author":"V Dostal","year":"2010","unstructured":"Dostal, V., Roberts, C. M. & Link, C. D. Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of \u00df-amyloid peptide toxicity. Genetics 186(3), 857\u2013866 (2010).","journal-title":"Genetics"},{"issue":"3","key":"68561_CR65","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/s0197-4580(02)00225-7","volume":"24","author":"J Drake","year":"2003","unstructured":"Drake, J., Link, C. D. & Butterfield, D. A. Oxidative stress precedes fibrillar deposition of Alzheimer\u2019s disease amyloid beta-peptide (1\u201342) in a transgenic Caenorhabditis elegans model. Neurobiol. Aging 24(3), 415\u2013420. https:\/\/doi.org\/10.1016\/s0197-4580(02)00225-7 (2003).","journal-title":"Neurobiol. Aging"},{"key":"68561_CR66","doi-asserted-by":"publisher","DOI":"10.3791\/2496","author":"G Solis","year":"2011","unstructured":"Solis, G. & Petraschek, M. Measuring Caenorhabditis elegans life span in 96 well microtiter plates. JoVE https:\/\/doi.org\/10.3791\/2496 (2011).","journal-title":"JoVE"},{"issue":"50","key":"68561_CR67","doi-asserted-by":"publisher","first-page":"13102","DOI":"10.1523\/JNEUROSCI.3448-06.2006","volume":"26","author":"Y Wu","year":"2006","unstructured":"Wu, Y. et al. Amyloid-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50), 13102\u201313113. https:\/\/doi.org\/10.1523\/JNEUROSCI.3448-06.2006 (2006).","journal-title":"J. Neurosci."},{"key":"68561_CR68","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1002\/0471142727","volume":"109","author":"DC Conte","year":"2017","unstructured":"Conte, D. C. et al. RNA Interference in Caenorhabditis Elegans. Curr. Protoc. Mol. Biol. 109, 2631\u201326330. https:\/\/doi.org\/10.1002\/0471142727 (2017).","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"68561_CR69","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot5439","author":"DC Rio","year":"2010","unstructured":"Rio, D. C., Hannon, G. J. & Nilsen, T. W. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb. Protoc. https:\/\/doi.org\/10.1101\/pdb.prot5439 (2010).","journal-title":"Cold Spring Harb. Protoc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68561-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68561-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68561-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T14:12:46Z","timestamp":1670335966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68561-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,16]]},"references-count":69,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["68561"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-68561-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,16]]},"assertion":[{"value":"11 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11707"}}