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PLoS One 2011; 6: e17010.","DOI":"10.1371\/journal.pone.0017010"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5 Martin KR, Corlett A, Dubach D, et al. Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. Hum Mol Genet 2012; 21: 3025\u20133041.","DOI":"10.1093\/hmg\/dds134"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6 Ahn KJ, Jeong HK, Choi HS, et al. DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis 2006; 22: 463\u2013472.","DOI":"10.1016\/j.nbd.2005.12.006"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7 Voronov SV, Frere SG, Giovedi S, et al. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down\u2019s syndrome. Proc Natl Acad Sci U S A 2008; 105: 9415\u20139420.","DOI":"10.1073\/pnas.0803756105"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8 Ema M, Ikegami S, Hosoya T, et al. Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down\u2019s syndrome. Hum Mol Genet 1999; 8: 1409\u20131415.","DOI":"10.1093\/hmg\/8.8.1409"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9 Kahlem P, Sultan M, Herwig R, et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res 2004; 14: 1258\u20131267.","DOI":"10.1101\/gr.1951304"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10 Birchler JA, Riddle NC, Auger DL, Veitia RA. Dosage balance in gene regulation: biological implications. Trends Genet 2005; 21: 219\u2013226.","DOI":"10.1016\/j.tig.2005.02.010"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11 Wang P, Wang F, Ni L, Wu P, Chen J. Targeting redox-altered plasticity to reactivate synaptic function: a novel therapeutic strategy for cognitive disorder. 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Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. <i>Am J Med Genet A<\/i> 2011; <b>155A<\/b>: 1939\u20131948.","DOI":"10.1002\/ajmg.a.34114"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30 Barnham KJ, Bush AI. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem Soc Rev 2014; 43: 6727\u20136749.","DOI":"10.1039\/C4CS00138A"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31 Saghazadeh A, Mahmoudi M, Dehghani Ashkezari A, Oliaie Rezaie N, Rezaei N. Systematic review and meta-analysis shows a specific micronutrient profile in people with Down Syndrome: lower blood calcium, selenium and zinc, higher red blood cell copper and zinc, and higher salivary calcium and sodium. PLoS One 2017; 12: e0175437.","DOI":"10.1371\/journal.pone.0175437"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32 Fang YZ, Yang S, Wu G. Free radicals, antioxidants, and nutrition. Nutrition 2002; 18: 872\u2013879.","DOI":"10.1016\/S0899-9007(02)00916-4"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33 Chiueh CC. Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol 2001; 25: 138\u2013147.","DOI":"10.1016\/S0887-8994(01)00266-1"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34 Manna C, Officioso A, Trojsi F, et al. Increased non-protein bound iron in Down syndrome: contribution to lipid peroxidation and cognitive decline. Free Radic Res 2016; 50: 1422\u20131431.","DOI":"10.1080\/10715762.2016.1253833"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35 Gaetke LM, Chow CK. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology 2003; 189: 147\u2013163.","DOI":"10.1016\/S0300-483X(03)00159-8"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36 Ozcelik D, Uzun H. Copper intoxication; antioxidant defenses and oxidative damage in rat brain. 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J Neurosci 2005; 25: 4375\u20134384.","DOI":"10.1523\/JNEUROSCI.0115-05.2005"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43 Medalia A, Galynker I, Scheinberg IH. The interaction of motor, memory, and emotional dysfunction in Wilson\u2019s disease. Biol Psychiatry 1992; 31: 823\u2013826.","DOI":"10.1016\/0006-3223(92)90313-O"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44 Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer\u2019s disease transgenic mice. Neuron 2001; 30: 665\u2013676.","DOI":"10.1016\/S0896-6273(01)00317-8"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45 Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT. Redox-active metals, oxidative stress, and Alzheimer\u2019s disease pathology. Ann N Y Acad Sci 2004; 1012: 153\u2013163.","DOI":"10.1196\/annals.1306.012"},{"key":"46","doi-asserted-by":"crossref","unstructured":"46 Morris MC, Evans DA, Tangney CC, et al. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch Neurol 2006; 63: 1085\u20131088.","DOI":"10.1001\/archneur.63.8.1085"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47 Sheppard O, Plattner F, Rubin A, <i>et al.<\/i> Altered regulation of tau phosphorylation in a mouse model of down syndrome aging. <i>Neurobiol Aging<\/i> 2012; <b>33<\/b>: 828.e31\u201344.","DOI":"10.1016\/j.neurobiolaging.2011.06.025"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48 O&apos;Doherty A, Ruf S, Mulligan C, et al. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 2005; 309: 2033\u20132037.","DOI":"10.1126\/science.1114535"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49 Liu F, Liang Z, Wegiel J, et al. 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