{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T16:31:22Z","timestamp":1781281882136,"version":"3.54.1"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T00:00:00Z","timestamp":1499126400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T00:00:00Z","timestamp":1499126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Late-onset Alzheimer\u2019s disease (AD) remains a medical mystery. Recent studies have linked it to impaired repair of aged neurons. Potential involvement of interleukin33 (IL33) in AD has been reported. Here we show that IL33, which was expressed by up to 75% astrocytes in the aged brains, was critical for repair of aged neurons. Mice lacking <jats:italic>Il33<\/jats:italic> gene (<jats:italic>Il33<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) developed AD-like disease after 60\u201380 weeks, which was characterized by tau abnormality and a heavy loss of neurons\/neurites in the cerebral cortex and hippocampus accompanied with cognition\/memory impairment. We detected an abrupt aging surge in the cortical and hippocampal neurons at middle age (40 weeks). To counter the aging surge, wild-type mice rapidly upregulated repair of DNA double-strand breaks (DSBs) and autophagic clearance of cellular wastes in these neurons. <jats:italic>Il33<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice failed to do so, but instead went on to develop rapid accumulation of abnormal tau, massive DSBs and abnormal autophagic vacuoles in these neurons. Thus, uncontrolled neuronal aging surge at middle age due to lack of IL33 resulted in neurodegeneration and late-onset AD-like symptome in <jats:italic>Il33<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Our study also suggests that the aging surge is a time to search for biomarkers for early diagnosis of AD before massive neuron loss.<\/jats:p>","DOI":"10.1038\/tp.2017.142","type":"journal-article","created":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T13:40:44Z","timestamp":1499175644000},"page":"e1164-e1164","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice"],"prefix":"10.1038","volume":"7","author":[{"given":"C","family":"Carlock","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Shim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Moreno-Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M R","family":"Pitcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Hicks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Quevado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-2425","authenticated-orcid":false,"given":"Y","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,4]]},"reference":[{"key":"BFtp2017142_CR1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.jalz.2015.02.003","volume":"11","author":"Alzheimer\u2019s Association","year":"2016","unstructured":"Alzheimer\u2019s Association. 2015 Alzheimer\u2019s disease facts and figures. Alzheimers Dement 2016; 11: 332\u2013384.","journal-title":"Alzheimers Dement"},{"key":"BFtp2017142_CR2","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nm.3232","volume":"19","author":"RA Nixon","year":"2013","unstructured":"Nixon RA . The role of autophagy in neurodegenerative disease. Nat Med 2013; 19: 983\u2013997.","journal-title":"Nat Med"},{"key":"BFtp2017142_CR3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1172\/JCI73944","volume":"125","author":"RA Frake","year":"2015","unstructured":"Frake RA, Ricketts T, Menzies FM, Rubinsztein DC . Autophagy and neurodegeneration. J Clin Invest 2015; 125: 65\u201374.","journal-title":"J Clin Invest"},{"key":"BFtp2017142_CR4","doi-asserted-by":"publisher","first-page":"36","DOI":"10.2174\/156720509787313970","volume":"6","author":"F Coppede","year":"2009","unstructured":"Coppede F, Migliore L . DNA damage and repair in Alzheimer\u2019s disease. Curr Alzheimer Res 2009; 6: 36\u201347.","journal-title":"Curr Alzheimer Res"},{"key":"BFtp2017142_CR5","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1523\/JNEUROSCI.16-05-01710.1996","volume":"16","author":"AJ Anderson","year":"1996","unstructured":"Anderson AJ, Su H, Cotman CW . DNA damage and apoptosis in Alzheimer\u2019s disease: colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay. J Neurosci 1996; 16: 1710\u20131719.","journal-title":"J Neurosci"},{"key":"BFtp2017142_CR6","doi-asserted-by":"publisher","first-page":"8897","DOI":"10.1038\/ncomms9897","volume":"6","author":"E Suberbielle","year":"2015","unstructured":"Suberbielle E, Djukic B, Evans M, Kim DH, Taneja P, Wang X et al. DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nat Commun 2015; 6: 8897.","journal-title":"Nat Commun"},{"key":"BFtp2017142_CR7","doi-asserted-by":"publisher","first-page":"397","DOI":"10.3109\/00207450903411133","volume":"120","author":"M Obulesu","year":"2010","unstructured":"Obulesu M, Rao DM . DNA damage and impairment of DNA repair in Alzheimer\u2019s disease. Int J Neurosci 2010; 120: 397\u2013403.","journal-title":"Int J Neurosci"},{"key":"BFtp2017142_CR8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.mad.2016.04.005","volume":"161","author":"Y Hou","year":"2017","unstructured":"Hou Y, Song H, Croteau DL, Akbari M, Bohr VA . Genome instability in Alzheimer disease. Mech Ageing Dev 2017; 161: 83\u201394.","journal-title":"Mech Ageing Dev"},{"key":"BFtp2017142_CR9","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/nrneurol.2012.35","volume":"8","author":"K Malpass","year":"2012","unstructured":"Malpass K . Alzheimer disease: DNA damage provides novel and powerful biomarkers of Alzheimer disease. Nat Rev Neurol 2012; 8: 178.","journal-title":"Nat Rev Neurol"},{"key":"BFtp2017142_CR10","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1172\/JCI200318182","volume":"111","author":"JA Klein","year":"2003","unstructured":"Klein JA, Ackerman SL . Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest 2003; 111: 785\u2013793.","journal-title":"J Clin Invest"},{"key":"BFtp2017142_CR11","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.cell.2015.08.069","volume":"163","author":"P Ejlerskov","year":"2015","unstructured":"Ejlerskov P, Hultberg JG, Wang JY, Carlsson R, Ambjorn M, Kuss M et al. Lack of neuronal IFN-\u03b2-IFNAR causes Lewy Body- and Parkinson\u2019s disease-like dementia. Cell 2015; 163: 324\u2013329.","journal-title":"Cell"},{"key":"BFtp2017142_CR12","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1038\/nm.2965","volume":"18","author":"J Vom Berg","year":"2012","unstructured":"Vom Berg J, Prokop S, Miller KR, Obst J, K\u00e4lin RE, Lopategui-Cabezas I et al. Inhibition of IL-12\/IL-23 signaling reduces Alzheimer\u2019s disease-like pathology and cognitive decline. Nat Med 2012; 18: 1812\u20131819.","journal-title":"Nat Med"},{"key":"BFtp2017142_CR13","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cell.2013.03.030","volume":"153","author":"B Zhang","year":"2013","unstructured":"Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer\u2019s disease. Cell 2013; 153: 707\u2013720.","journal-title":"Cell"},{"key":"BFtp2017142_CR14","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3233\/JAD-2011-101815","volume":"25","author":"K Morimoto","year":"2011","unstructured":"Morimoto K, Horio J, Satoh H, Sue L, Beach T, Arita S et al. Expression profiles of cytokines in the brains of Alzheimer\u2019s disease (AD) patients compared to the brains of non-demented patients with and without increasing AD pathology. J Alzheimers Dis 2011; 25: 59\u201376.","journal-title":"J Alzheimers Dis"},{"key":"BFtp2017142_CR15","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.neuron.2015.01.013","volume":"85","author":"SP Gadani","year":"2015","unstructured":"Gadani SP, Walsh JT, Smirnov I, Zheng J, Kipnis J . The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 2015; 85: 703\u2013709.","journal-title":"Neuron"},{"key":"BFtp2017142_CR16","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1084\/jem.20150894","volume":"213","author":"H Xi","year":"2016","unstructured":"Xi H, Katschke KJ Jr, Li Y, Truong T, Lee WP, Diehl L et al. IL-33 amplifies an innate immune response in the degenerating retina. J Exp Med 2016; 213: 189\u2013207.","journal-title":"J Exp Med"},{"key":"BFtp2017142_CR17","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1002\/eji.201141947","volume":"42","author":"HR Jiang","year":"2012","unstructured":"Jiang HR, Milovanovi\u0107 M, Allan D, Niedbala W, Besnard AG, Fukada SY et al. IL-33 attenuates EAE by suppressing IL-17 and IFN-\u03b3 production and inducing alternatively activated macrophages. Eur J Immunol 2012; 42: 1804\u20131814.","journal-title":"Eur J Immunol"},{"key":"BFtp2017142_CR18","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.jneuroim.2014.08.035","volume":"275","author":"B Stojanovic","year":"2014","unstructured":"Stojanovic B, Milovovic J, Arsenijevic A, Milovovic M, Arsenijevic N, Lukic ML . IL-33\/ST2 axis mediates resistance to EAE by promoting regulatory B and tolerogenic dendritic cells. Neuroimmunol 2014; 275: 11\u201312.","journal-title":"Neuroimmunol"},{"key":"BFtp2017142_CR19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jneuroim.2012.03.016","volume":"247","author":"M Li","year":"2012","unstructured":"Li M, Li Y, Liu X, Gao X, Wang Y . IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL\/6 mice. J Neuroimmunol 2012; 247: 25\u201331.","journal-title":"J Neuroimmunol"},{"key":"BFtp2017142_CR20","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/mp.2009.10","volume":"14","author":"J Chapuis","year":"2009","unstructured":"Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C et al. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer\u2019s disease. Mol Psychiatry 2009; 14: 1004\u20131016.","journal-title":"Mol Psychiatry"},{"key":"BFtp2017142_CR21","doi-asserted-by":"publisher","first-page":"E2705","DOI":"10.1073\/pnas.1604032113","volume":"113","author":"AK Fu","year":"2016","unstructured":"Fu AK, Hung K, Yuen MYF, Zhou X, Mak DSY, Chan ICW et al. IL-33 ameliorates Alzheimer\u2019s disease-like pathology and cognitive decline. Proc Natl Acad Sci USA 2016; 113: E2705\u2013E2713.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp2017142_CR22","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.neulet.2013.09.046","volume":"555","author":"G Wicher","year":"2013","unstructured":"Wicher G, Husic E, Nilsson G, Forsberg-Nilsson K . Developmental expression of IL-33 in the mouse brain. Neurosci Lett 2013; 555: 171\u2013176.","journal-title":"Neurosci Lett"},{"key":"BFtp2017142_CR23","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3233\/JAD-132081","volume":"40","author":"Z Xiong","year":"2014","unstructured":"Xiong Z, Thangavel R, Kempuraj D, Yang E, Zaheer S, Zaheer A et al. Alzheimer\u2019s disease: evidence for the expression of interleukin-33 and its receptor ST2 in the brain. J Alzheimers Dis 2014; 40: 297\u2013308.","journal-title":"J Alzheimers Dis"},{"key":"BFtp2017142_CR24","doi-asserted-by":"publisher","first-page":"3488","DOI":"10.4049\/jimmunol.1101977","volume":"188","author":"M Pichery","year":"2012","unstructured":"Pichery M, Mirey M, Mercier P, Lefrancais E, Dujardin A, Ortega N et al. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33\u2013LacZ gene trap reporter strain. J Immunol 2012; 188: 3488\u20133495.","journal-title":"J Immunol"},{"key":"BFtp2017142_CR25","doi-asserted-by":"publisher","first-page":"e3331","DOI":"10.1371\/journal.pone.0003331","volume":"3","author":"C Moussion","year":"2008","unstructured":"Moussion C, Ortega N, Girard JP . The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel \u2018alarmin\u2019? PLoS ONE 2008; 3: e3331.","journal-title":"PLoS ONE"},{"key":"BFtp2017142_CR26","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.brainres.2011.02.045","volume":"1385","author":"S Yasuoka","year":"2011","unstructured":"Yasuoka S, Kawanokuchi J, Parajuli B, Suzumura A . Production and functions of IL-33 in the central nervous system. Brain Res 2011; 1385: 8\u201317.","journal-title":"Brain Res"},{"key":"BFtp2017142_CR27","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/ni.3370","volume":"17","author":"NT Martin","year":"2016","unstructured":"Martin NT, Martin MU . Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol 2016; 17: 122\u2013131.","journal-title":"Nat Immunol"},{"key":"BFtp2017142_CR28","doi-asserted-by":"publisher","first-page":"161","DOI":"10.4049\/jimmunol.1400381","volume":"193","author":"C Carlock","year":"2014","unstructured":"Carlock C, Wu J, Zhou C, Tatum K, Adams HP, Tan F et al. Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J Immunol 2014; 193: 161\u2013169.","journal-title":"J Immunol"},{"key":"BFtp2017142_CR29","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.4049\/jimmunol.1402503","volume":"194","author":"J Wu","year":"2015","unstructured":"Wu J, Carlock C, Zhou C, Nakae S, Hicks J, Adams HP et al. Interleukin33 is required for disposal of unnecessary cells during ovarian atresia through regulation of autophagy and macrophage migration. J Immunol 2015; 194: 2140\u20132147.","journal-title":"J Immunol"},{"key":"BFtp2017142_CR30","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1038\/nbt822","volume":"21","author":"DM Valenzuela","year":"2003","unstructured":"Valenzuela DM, Murphy AJ, Frendewey D, Gale NW, Economides AN, Auerbach W et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat Biotechnol 2003; 21: 652\u2013659.","journal-title":"Nat Biotechnol"},{"key":"BFtp2017142_CR31","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.1073\/pnas.1003059107","volume":"107","author":"K Oboki","year":"2010","unstructured":"Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A et al. IL33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci USA 2010; 107: 1858\u20131856.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp2017142_CR32","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.bbr.2013.02.008","volume":"245","author":"D Cheng","year":"2013","unstructured":"Cheng D, Logge W, Low JK, Garner B, Karl T . Novel behavioural characteristics of the APPSwe\/PS1\u0394E9 transgenic mouse model of Alzheimer\u2019s disease. Behav Brain Res 2013; 245: 120\u2013127.","journal-title":"Behav Brain Res"},{"key":"BFtp2017142_CR33","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.brainres.2006.10.085","volume":"1130","author":"M Hrnkova","year":"2007","unstructured":"Hrnkova M, Zilka N, Minichova Z, Koson P, Novak M . Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res 2007; 1130: 206\u2013213.","journal-title":"Brain Res"},{"key":"BFtp2017142_CR34","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.bbr.2007.08.003","volume":"186","author":"Y Senechal","year":"2008","unstructured":"Senechal Y, Kelly PH, Dev KK . Amyloid precursor protein knockout mice show age-dependent deficits in passive avoidance learning. Behav Brain Res 2008; 186: 126\u2013132.","journal-title":"Behav Brain Res"},{"key":"BFtp2017142_CR35","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1083\/jcb.30.2.405","volume":"30","author":"H Lovtrup-Rein","year":"1966","unstructured":"Lovtrup-Rein H, McEwen BS . Isolation and fractionation of rat brain nuclei. J Cell Biol 1966; 30: 405\u2013415.","journal-title":"J Cell Biol"},{"key":"BFtp2017142_CR36","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1083\/jcb.93.1.144","volume":"93","author":"L Marzella","year":"1982","unstructured":"Marzella L, Ahlberg J, Glaumann H . Isolation of autophagic vacuoles from rat liver: morphological and biochemical characterization. J Cell Biol 1982; 93: 144\u2013154.","journal-title":"J Cell Biol"},{"key":"BFtp2017142_CR37","doi-asserted-by":"publisher","first-page":"3300","DOI":"10.1093\/brain\/awu278","volume":"137","author":"DS Yang","year":"2014","unstructured":"Yang DS, Stavrides P, Saito M, Kumar A, Rodriguez-Navarro JA, Pawlik M et al. Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 2014; 137: 3300\u20133318.","journal-title":"Brain"},{"key":"BFtp2017142_CR38","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1037\/0735-7044.121.2.340","volume":"121","author":"FJ Gil-Bea","year":"2007","unstructured":"Gil-Bea FJ, Aisa B, Schliebs R, Ramirez MJ . Increase of locomotor activity underlying the behavioral disinhibition in tg2576 mice. Behav Neurosci 2007; 121: 340\u2013344.","journal-title":"Behav Neurosci"},{"key":"BFtp2017142_CR39","doi-asserted-by":"publisher","first-page":"e59586","DOI":"10.1371\/journal.pone.0059586","volume":"8","author":"AL Wright","year":"2013","unstructured":"Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP et al. Neuroinflammation and neuronal loss precede A\u03b2 plaque deposition in the hAPP-J20 mouse model of Alzheimer\u2019s disease. PLoS ONE 2013; 8: e59586.","journal-title":"PLoS ONE"},{"key":"BFtp2017142_CR40","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1096\/fj.05-4265fje","volume":"20","author":"YH Jeong","year":"2006","unstructured":"Jeong YH, Park CH, Yoo J, Shin KY, Ahn SM, Kim HS et al. Chronic stress accelerates learning and memory impairments and increases amyloid deposition in APPV717I-CT100 transgenic mice, an Alzheimer\u2019s disease model. FASEB J 2006; 20: 729\u2013731.","journal-title":"FASEB J"},{"key":"BFtp2017142_CR41","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/BF02736774","volume":"8","author":"WP Li","year":"1997","unstructured":"Li WP, Chan WY, Lai HW, Yew DT . Terminal dUTP nick end labeling (TUNEL) positive cells in the different regions of the brain in normal aging and Alzheimer patients. J Mol Neurosci 1997; 8: 75\u201382.","journal-title":"J Mol Neurosci"},{"key":"BFtp2017142_CR42","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1523\/JNEUROSCI.5066-07.2008","volume":"28","author":"DM Wilcock","year":"2008","unstructured":"Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N et al. Progression of amyloid pathology to Alzheimer\u2019s pathology in an APP transgenic mouse model by removal of NOS2. J Neurosci 2008; 28: 1537\u20131545.","journal-title":"J Neurosci"},{"key":"BFtp2017142_CR43","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1155\/S1110724302203010","volume":"2","author":"G Perry","year":"2002","unstructured":"Perry G, Cash AD, Smith MA . Alzheimer disease and oxidative stress. J Biomed Biotechnol 2002; 2: 120\u2013123.","journal-title":"J Biomed Biotechnol"},{"key":"BFtp2017142_CR44","doi-asserted-by":"publisher","first-page":"292","DOI":"10.3389\/fnagi.2014.00292","volume":"6","author":"PB Campos","year":"2014","unstructured":"Campos PB, Paulsen BS, Rehen SK . Accelerating neuronal aging in in vitro model brain disorders: a focus on reactive oxygen species. Front Aging Neurosci 2014; 6: 292.","journal-title":"Front Aging Neurosci"},{"key":"BFtp2017142_CR45","doi-asserted-by":"publisher","first-page":"5678","DOI":"10.1093\/nar\/gkn550","volume":"36","author":"A Kinner","year":"2008","unstructured":"Kinner A, Wu W, Staudt C, Iliakis G . \u03b3-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 2008; 36: 5678\u20135694.","journal-title":"Nucleic Acids Res"},{"key":"BFtp2017142_CR46","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/cgt.2011.51","volume":"18","author":"B Ladd","year":"2011","unstructured":"Ladd B, O\u2019Konek JJ, Ostruszka LJ, Shewach DS . Unrepairable DNA double-strand breaks initiate cytotoxicity with HSV-TKganciclovir. Cancer Gene Ther 2011; 18: 751\u2013759.","journal-title":"Cancer Gene Ther"},{"key":"BFtp2017142_CR47","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","volume":"83","author":"R Madabhusshi","year":"2011","unstructured":"Madabhusshi R, Pan L, Tsai L . DNA damage and its links to neurodegeneration. Neuron 2011; 83: 266\u2013282.","journal-title":"Neuron"},{"key":"BFtp2017142_CR48","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.ajhg.2008.01.009","volume":"82","author":"A Kulkarni","year":"2008","unstructured":"Kulkarni A, Wilson DM III . The involvement of DNA-damage and -repair defects in neurological dysfunction. Am J Hum Genet 2008; 82: 539\u2013566.","journal-title":"Am J Hum Genet"},{"key":"BFtp2017142_CR49","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nature04723","volume":"441","author":"M Komatsu","year":"2006","unstructured":"Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880\u2013884.","journal-title":"Nature"},{"key":"BFtp2017142_CR50","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1750-1326-7-48","volume":"7","author":"K Inoue","year":"2012","unstructured":"Inoue K, Rispoli J, Kaphzan H, Klann E, Chen EI, Kim J et al. Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol Neurodegen 2012; 7: 48.","journal-title":"Mol Neurodegen"},{"key":"BFtp2017142_CR51","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/nm1438","volume":"12","author":"RJ Bateman","year":"2006","unstructured":"Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM . Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 2006; 12: 856\u2013861.","journal-title":"Nat Med"},{"key":"BFtp2017142_CR52","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1016\/j.biocel.2004.05.009","volume":"36","author":"I Tanida","year":"2004","unstructured":"Tanida I, Ueno T, Kominami E . LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004; 36: 2503\u20132518.","journal-title":"Int J Biochem Cell Biol"},{"key":"BFtp2017142_CR53","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1093\/ilar.43.2.89","volume":"43","author":"JA Richardson","year":"2002","unstructured":"Richardson JA, Burns DK . Mouse models of Alzheimer\u2019s disease: a quest for plaques and tangles. ILAR J 2002; 43: 89\u201399.","journal-title":"ILAR J"},{"key":"BFtp2017142_CR54","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/nrn2420","volume":"9","author":"J Gotz","year":"2008","unstructured":"Gotz J, Ittner LM . Animal models of Alzheimer\u2019s disease and frontotemporal dementia. Rev Neurosci 2008; 9: 532\u2013544.","journal-title":"Rev Neurosci"},{"key":"BFtp2017142_CR55","doi-asserted-by":"publisher","first-page":"4050","DOI":"10.1523\/JNEUROSCI.20-11-04050.2000","volume":"20","author":"L Mucke","year":"2000","unstructured":"Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050\u20134058.","journal-title":"J Neurosci"}],"updated-by":[{"DOI":"10.1038\/tp.2017.176","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T00:00:00Z","timestamp":1501545600000}}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/tp2017142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/tp2017142","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/tp.2017.142","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/tp2017142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T17:00:26Z","timestamp":1671728426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/tp2017142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,4]]},"references-count":55,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2017,7]]}},"alternative-id":["BFtp2017142"],"URL":"https:\/\/doi.org\/10.1038\/tp.2017.142","relation":{"erratum":[{"id-type":"doi","id":"10.1038\/tp.2017.176","asserted-by":"object"}]},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,4]]},"assertion":[{"value":"12 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}