{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:12:23Z","timestamp":1790403143966,"version":"4.1.0"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"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":["BMC Neurol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer\u2019s disease (AD).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In this study, we used our state-of-the-art proteomic platform, a liquid chromatography\/mass spectrometry (LC-MS\/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 \u00b1 0.6\u2009yrs), age-matched controls (77.0 \u00b1 0.5\u2009yrs), and nonagenarian cases (93.2 \u00b1 1.1\u2009yrs).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Ingenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose\/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matched-control vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc <jats:italic>\u03b3<\/jats:italic>-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles\/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12883-020-01849-3","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T08:02:51Z","timestamp":1598515371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients"],"prefix":"10.1186","volume":"20","author":[{"given":"Andrew","family":"Pearson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Ajoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gogce","family":"Crynen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon M.","family":"Reed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustafa","family":"Algamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mullan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dushyant","family":"Purohit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8168-0954","authenticated-orcid":false,"given":"Joseph O.","family":"Ojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"1849_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/s00401-018-1812-4","volume":"135","author":"NJ Abbott","year":"2018","unstructured":"Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a \u2018glymphatic\u2019 system? Acta Neuropathol. 2018;135:387\u2013407. https:\/\/doi.org\/10.1007\/s00401-018-1812-4.","journal-title":"Acta Neuropathol"},{"key":"1849_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2045-8118-11-10","volume":"11","author":"T Brinker","year":"2014","unstructured":"Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:1\u201316. https:\/\/doi.org\/10.1186\/2045-8118-11-10.","journal-title":"Fluids Barriers CNS"},{"issue":"1","key":"1849_CR3","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s00401-009-0522-3","volume":"118","author":"RD Bell","year":"2009","unstructured":"Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer\u2019s disease. Acta Neuropathol. 2009;118(1):103\u201313.","journal-title":"Acta Neuropathol"},{"key":"1849_CR4","doi-asserted-by":"publisher","unstructured":"Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H, Nicholson C, Zlokovic BV, Frangione B, Blennow K, M\u00e9nard J, Zetterberg H, Wisniewski T, de Leon MJ. Clearance systems in the brain\u2014implications for Alzheimer disease. Nat Rev Neurol. 2015. https:\/\/doi.org\/10.1038\/nrneurol.2015.119.","DOI":"10.1038\/nrneurol.2015.119"},{"issue":"4","key":"1849_CR5","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.tins.2005.02.001","volume":"28","author":"BV Zlokovic","year":"2005","unstructured":"Zlokovic BV. Neurovascular mechanisms of Alzheimer\u2019s neurodegeneration. Trends Neurosci. 2005;28(4):202\u20138.","journal-title":"Trends Neurosci"},{"key":"1849_CR6","doi-asserted-by":"publisher","unstructured":"Ikeda K, Akiyama H, Kondo H, Haga C, Tanno E, Tokuda T, Ikeda S. Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol. 1995. https:\/\/doi.org\/10.1007\/BF00318575.","DOI":"10.1007\/BF00318575"},{"key":"1849_CR7","doi-asserted-by":"publisher","unstructured":"Kovacs GG, Majtenyi K, Spina S, Murrell JR, Gelpi E, Hoftberger R, Fraser G, Crowther RA, Goedert M, Budka H, Ghetti B. White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar segeneration. J Neuropathol Exp Neurol. 2008. https:\/\/doi.org\/10.1097\/NEN.0b013e318187a80f.","DOI":"10.1097\/NEN.0b013e318187a80f"},{"issue":"4","key":"1849_CR8","first-page":"295","volume":"49","author":"D Ma\u015bli\u0144ska","year":"2011","unstructured":"Ma\u015bli\u0144ska D, Laure-Kamionowska M, Taraszewska A, Der\u0229gowski K, Ma\u015bli\u0144ski S. Immunodistribution of amyloid beta protein (A\u03b2) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients. Folia Neuropathol. 2011;49(4):295\u2013300.","journal-title":"Folia Neuropathol"},{"key":"1849_CR9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s00401-015-1515-z","volume":"131","author":"AC McKee","year":"2016","unstructured":"McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Dirk Keene C, Litvan I, Perl DP, Stein TD, Vonsattel J-P, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O\u2019Connor K, Alvarez VE, Gordon WA. The first NINDS\/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 2016;131:75\u201386. https:\/\/doi.org\/10.1007\/s00401-015-1515-z.","journal-title":"Acta Neuropathol"},{"key":"1849_CR10","doi-asserted-by":"publisher","unstructured":"Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J. Contribution of glial cells to the development of amyloid plaques in Alzheimer\u2019s disease. Neurobiol Aging. 2004. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2004.01.007.","DOI":"10.1016\/j.neurobiolaging.2004.01.007"},{"issue":"7","key":"1849_CR11","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","volume":"9","author":"L Pantoni","year":"2010","unstructured":"Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689\u2013701.","journal-title":"Lancet Neurol"},{"key":"1849_CR12","doi-asserted-by":"publisher","first-page":"114","DOI":"10.3389\/fnagi.2018.00114","volume":"10","author":"BG Perez-Nievas","year":"2018","unstructured":"Perez-Nievas BG, Serrano-Pozo A. Deciphering the astrocyte reaction in Alzheimer\u2019s disease. Front Aging Neurosci. 2018;10:114.","journal-title":"Front Aging Neurosci"},{"key":"1849_CR13","doi-asserted-by":"publisher","unstructured":"Schultz C, Dehghani F, Hubbard GB, Thal DR, Struckhoff G, Braak E, Braak H. Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons. J Neuropathol Exp Neurol. 2000. https:\/\/doi.org\/10.1093\/jnen\/59.1.39.","DOI":"10.1093\/jnen\/59.1.39"},{"key":"1849_CR14","doi-asserted-by":"publisher","unstructured":"S\u00f6llvander S, Nikitidou E, Brolin R, S\u00f6derberg L, Sehlin D, Lannfelt L, Erlandsson A. Accumulation of amyloid-\u03b2 by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016. https:\/\/doi.org\/10.1186\/s13024-016-0098-z.","DOI":"10.1186\/s13024-016-0098-z"},{"key":"1849_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1743-8454-5-10","volume":"5","author":"CE Johanson","year":"2008","unstructured":"Johanson CE, Duncan JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5:1\u201332. https:\/\/doi.org\/10.1186\/1743-8454-5-10.","journal-title":"Cerebrospinal Fluid Res"},{"key":"1849_CR16","doi-asserted-by":"publisher","first-page":"39","DOI":"10.29245\/2572.942x\/2018\/4.1194","volume":"3","author":"C Johanson","year":"2018","unstructured":"Johanson C. Choroid plexus blood-CSF barrier: major player in brain disease modeling and Neuromedicine. J Neurol Neuromedicine. 2018;3:39\u201358. https:\/\/doi.org\/10.29245\/2572.942x\/2018\/4.1194.","journal-title":"J Neurol Neuromedicine"},{"key":"1849_CR17","doi-asserted-by":"publisher","first-page":"17553","DOI":"10.1523\/JNEUROSCI.3258-13.2013","volume":"33","author":"MK Lehtinen","year":"2013","unstructured":"Lehtinen MK, Bjornsson CS, Dymecki SM, Gilbertson RJ, Holtzman DM, Monuki ES. The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci. 2013;33:17553\u20139. https:\/\/doi.org\/10.1523\/JNEUROSCI.3258-13.2013.","journal-title":"J Neurosci"},{"key":"1849_CR18","doi-asserted-by":"publisher","unstructured":"Balusu S, Van Wonterghem E, De Rycke R, Raemdonck K, Stremersch S, Gevaert K, Brkic M, Demeestere D, Vanhooren V, Hendrix A, Libert C, Vandenbroucke RE. Identification of a novel mechanism of blood\u2013brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Mol Med. 2016. https:\/\/doi.org\/10.15252\/emmm.201606271.","DOI":"10.15252\/emmm.201606271"},{"issue":"8","key":"1849_CR19","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1517\/14712598.4.8.1191","volume":"4","author":"DF Emerich","year":"2004","unstructured":"Emerich DF, Vasconcellos AV, Elliott RB, Skinner SJM, Borlongan CV. The choroid plexus: function, pathology and therapeutic potential of its transplantation. Expert Opin Biol Ther. 2004;4(8):1191\u2013201.","journal-title":"Expert Opin Biol Ther"},{"key":"1849_CR20","doi-asserted-by":"publisher","unstructured":"Krzyzanowska A, Carro E. Pathological alteration in the choroid plexus of Alzheimer\u2019s disease: implication for new therapy approaches. Front Pharmacol. 2012. https:\/\/doi.org\/10.3389\/fphar.2012.00075.","DOI":"10.3389\/fphar.2012.00075"},{"issue":"suppl","key":"1849_CR21","first-page":"s515","volume":"8","author":"JM Serot","year":"2003","unstructured":"Serot JM, B\u00e9n\u00e9 MC, Faure GC. Choroid plexus, ageing of the brain, and Alzheimer\u2019s disease. Front Biosci. 2003;8(suppl):s515\u201321.","journal-title":"Front Biosci"},{"key":"1849_CR22","volume-title":"Altered choroid plexus basement membrane and epithelium in late-onset Alzheimer\u2019s disease: an ultrastructural study. In: Annals of the New York Academy of Sciences","author":"JM Serot","year":"1997","unstructured":"Serot JM, B\u00e9n\u00e9 MC, Foliguet B, Faure GC. Altered choroid plexus basement membrane and epithelium in late-onset Alzheimer\u2019s disease: an ultrastructural study. In: Annals of the New York Academy of Sciences; 1997."},{"key":"1849_CR23","doi-asserted-by":"publisher","unstructured":"Serot JM, B\u00e9n\u00e9 MC, Foliguet B, Faure GC. Morphological alterations of the choroid plexus in late-onset Alzheimer\u2019s disease. Acta Neuropathol. 2000. https:\/\/doi.org\/10.1007\/PL00007412.","DOI":"10.1007\/PL00007412"},{"key":"1849_CR24","doi-asserted-by":"publisher","unstructured":"Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L, Ball MJ, Bierer LM, Claasen D, Hansen LR, Hart M, Hedreen J, Baltimore B, Hen Derson V, Hyman BT, Joachim C, Mark-Esbery W, Mar Tinez AJ, McKee A, Miller C, Moossy J, Nochlin D, Perl D, Petito C, Rao GR, Schelper RL, Slager U, Terry RD. The consortium to establish a registry for Alzheimer\u2019s disease (CERAD). Part II Standardization of the neuropathologic assessment of Alzheimer\u2019s disease. Neurology. 1991. https:\/\/doi.org\/10.1212\/wnl.41.4.479.","DOI":"10.1212\/wnl.41.4.479"},{"key":"1849_CR25","doi-asserted-by":"publisher","unstructured":"Ball M, Braak H, Coleman P, Dickson D, Duyckaerts C, Gambetti P, Hansen L, Hyman B, Jellinger K, Markesbery W, Perl D, Powers J, Price J, Trojanowski JQ, Wisniewski H, Phelps C, Khachaturian Z. Consensus recommendations for the postmortem diagnosis of Alzheimer\u2019s disease. Neurobiol Aging. 1997. https:\/\/doi.org\/10.1016\/S0197-4580(97)00057-2.","DOI":"10.1016\/S0197-4580(97)00057-2"},{"key":"1849_CR26","doi-asserted-by":"publisher","unstructured":"Braak H, Braak E. Staging of alzheimer\u2019s disease-related neurofibrillary changes. Neurobiol Aging. 1995. https:\/\/doi.org\/10.1016\/0197-4580(95)00021-6.","DOI":"10.1016\/0197-4580(95)00021-6"},{"key":"1849_CR27","doi-asserted-by":"publisher","unstructured":"Ojo JO, Crynen G, Reed JM, Ajoy R, Vallabhaneni P, Algamal M, Leary P, Rafi NG, Mouzon B, Mullan M, Crawford F. Unbiased proteomic approach identifies unique and coincidental plasma biomarkers in repetitive mTBI and AD pathogenesis. Front Aging Neurosci. 2018. https:\/\/doi.org\/10.3389\/fnagi.2018.00405.","DOI":"10.3389\/fnagi.2018.00405"},{"key":"1849_CR28","doi-asserted-by":"publisher","unstructured":"Zakirova Z, Reed J, Crynen G, Horne L, Hassan S, Mathura V, Mullan M, Crawford F, Ait-Ghezala G. Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of gulf war illness. Proteomics - Clin Appl. 2017;11. https:\/\/doi.org\/10.1002\/prca.201600190.","DOI":"10.1002\/prca.201600190"},{"key":"1849_CR29","doi-asserted-by":"publisher","unstructured":"Vizca\u00edno JA, Csordas A, Del-Toro N, Dianes JA, Griss J, Lavidas I, Mayer G, Perez-Riverol Y, Reisinger F, Ternent T, Xu QW, Wang R, Hermjakob H. 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2016. https:\/\/doi.org\/10.1093\/nar\/gkv1145.","DOI":"10.1093\/nar\/gkv1145"},{"key":"1849_CR30","doi-asserted-by":"publisher","unstructured":"Kr\u00e4mer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 2014. https:\/\/doi.org\/10.1093\/bioinformatics\/btt703.","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"1849_CR31","doi-asserted-by":"publisher","unstructured":"De Lange ECM. Utility of CSF in translational neuroscience. J Pharmacokinet Pharmacodyn. 2013. https:\/\/doi.org\/10.1007\/s10928-013-9301-9.","DOI":"10.1007\/s10928-013-9301-9"},{"key":"1849_CR32","doi-asserted-by":"publisher","unstructured":"Bozanovic-Sosic R, Mollanji R, Johnston MG. Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol - Regul Integr Comp Physiol. 2001. https:\/\/doi.org\/10.1152\/ajpregu.2001.281.3.r909.","DOI":"10.1152\/ajpregu.2001.281.3.r909"},{"issue":"4","key":"1849_CR33","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1152\/physrev.00004.2013","volume":"93","author":"HH Damkier","year":"2013","unstructured":"Damkier HH, Brown PD, Praetorius J. Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev. 2013;93(4):1847\u201392.","journal-title":"Physiol Rev"},{"key":"1849_CR34","doi-asserted-by":"publisher","unstructured":"Alvira-Botero X, M. Carro E. Clearance of amyloid-\u03b2 peptide across the choroid plexus in Alzheimers disease. Curr Aging Sci. 2010. https:\/\/doi.org\/10.2174\/1874609811003030219.","DOI":"10.2174\/1874609811003030219"},{"key":"1849_CR35","doi-asserted-by":"publisher","unstructured":"Stopa EG, Berzin TM, Kim S, Song P, Kuo-LeBlanc V, Rodriguez-Wolf M, Baird A, Johanson CE. Human choroid plexus growth factors: what are the implications for CSF dynamics in Alzheimer\u2019s disease? Exp Neurol. 2001. https:\/\/doi.org\/10.1006\/exnr.2000.7545.","DOI":"10.1006\/exnr.2000.7545"},{"key":"1849_CR36","doi-asserted-by":"publisher","unstructured":"Thouvenot E, Lafon-Cazal M, Demettre E, Jouin P, Bockaert J, Marin P. The proteomic analysis of mouse choroid plexus secretome reveals a high protein secretion capacity of choroidal epithelial cells. Proteomics. 2006. https:\/\/doi.org\/10.1002\/pmic.200600096.","DOI":"10.1002\/pmic.200600096"},{"key":"1849_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12864-015-2159-z","volume":"16","author":"AA Bergen","year":"2015","unstructured":"Bergen AA, Kaing S, ten Brink JB, Gorgels TG, Janssen SF. Gene expression and functional annotation of human choroid plexus epithelium failure in Alzheimer\u2019s disease. BMC Genomics. 2015;16:1\u201315. https:\/\/doi.org\/10.1186\/s12864-015-2159-z.","journal-title":"BMC Genomics"},{"key":"1849_CR38","doi-asserted-by":"publisher","unstructured":"Stopa EG, Tanis KQ, Miller MC, Nikonova EV, Podtelezhnikov AA, Finney EM, Stone DJ, Camargo LM, Parker L, Verma A, Baird A, Donahue JE, Torabi T, Eliceiri BP, Silverberg GD, Johanson CE. Comparative transcriptomics of choroid plexus in Alzheimer\u2019s disease, frontotemporal dementia and Huntington\u2019s disease: implications for CSF homeostasis. Fluids Barriers CNS. 2018. https:\/\/doi.org\/10.1186\/s12987-018-0102-9.","DOI":"10.1186\/s12987-018-0102-9"},{"key":"1849_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12987-018-0120-7","volume":"15","author":"S Kant","year":"2018","unstructured":"Kant S, Stopa EG, Johanson CE, Baird A, Silverberg GD. Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer\u2019s disease. Fluids Barriers CNS. 2018;15:1\u201310. https:\/\/doi.org\/10.1186\/s12987-018-0120-7.","journal-title":"Fluids Barriers CNS"},{"key":"1849_CR40","doi-asserted-by":"publisher","unstructured":"Krzyzanowska A, Garc\u00eda-Consuegra I, Pascual C, Antequera D, Ferrer I, Carro E. Expression of regulatory proteins in choroid plexus changes in early stages of alzheimer disease. J Neuropathol Exp Neurol. 2015. https:\/\/doi.org\/10.1097\/NEN.0000000000000181.","DOI":"10.1097\/NEN.0000000000000181"},{"key":"1849_CR41","doi-asserted-by":"publisher","unstructured":"Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD, Bronte-Stewart H, Rubenstein E, Possin K, Saul TA. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer\u2019s type. Neurology. 2001. https:\/\/doi.org\/10.1212\/WNL.57.10.1763.","DOI":"10.1212\/WNL.57.10.1763"},{"key":"1849_CR42","doi-asserted-by":"publisher","unstructured":"de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L, Osorio RS, Fortea J, Butler T, Pirraglia E, Fossati S, Kim H-J, Carare RO, Nedergaard M, Benveniste H, Rusinek H. CSF clearance in Alzheimer disease measured with dynamic PET 2 running title: impaired CSF clearance in. J Nucl Med. 2017. https:\/\/doi.org\/10.2967\/jnumed.116.187211.","DOI":"10.2967\/jnumed.116.187211"},{"key":"1849_CR43","doi-asserted-by":"publisher","unstructured":"Nakada T, Suzuki Y, Kwee IL. Patients show significant disturbance in water influx into CSF space, strongly supporting beta-amyloid clearance hypothesis. Alzheimer\u2019s Dement. 2014. https:\/\/doi.org\/10.1016\/j.jalz.2014.04.033.","DOI":"10.1016\/j.jalz.2014.04.033"},{"issue":"5","key":"1849_CR44","doi-asserted-by":"publisher","first-page":"e0123708","DOI":"10.1371\/journal.pone.0123708","volume":"10","author":"Y Suzuki","year":"2015","unstructured":"Suzuki Y, Nakamura Y, Yamada K, Igarashi H, Kasuga K, Yokoyama Y, Ikeuchi T, Nishizawa M, Kwee IL, Nakada T. Reduced CSF water influx in Alzheimer\u2019s disease supporting the \u03b2-amyloid clearance hypothesis. PLoS ONE. 2015;10(5):e0123708.","journal-title":"PLoS ONE"},{"key":"1849_CR45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1743-8454-3-7","volume":"3","author":"G Silverberg","year":"2006","unstructured":"Silverberg G, Mayo M, Saul T, Fellmann J, McGuire D. Elevated cerebrospinal fluid pressure in patients with Alzheimer\u2019s disease. Cerebrospinal Fluid Res. 2006;3:1\u20136. https:\/\/doi.org\/10.1186\/1743-8454-3-7.","journal-title":"Cerebrospinal Fluid Res"},{"key":"1849_CR46","doi-asserted-by":"publisher","unstructured":"Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-\u03b2 synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006. https:\/\/doi.org\/10.1038\/nm1438.","DOI":"10.1038\/nm1438"},{"key":"1849_CR47","doi-asserted-by":"publisher","unstructured":"Sato C, Barth\u00e9lemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM, Bateman RJ. Tau kinetics in neurons and the human central nervous system. Neuron. 2018. https:\/\/doi.org\/10.1016\/j.neuron.2018.02.015.","DOI":"10.1016\/j.neuron.2018.02.015"},{"key":"1849_CR48","doi-asserted-by":"publisher","unstructured":"Cottrell DA, Blakely EL, Johnson MA, Ince PG, Borthwick GM, Turnbull DM. Cytochrome C oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiol Aging. 2001. https:\/\/doi.org\/10.1016\/S0197-4580(00)00234-7.","DOI":"10.1016\/S0197-4580(00)00234-7"},{"key":"1849_CR49","doi-asserted-by":"publisher","unstructured":"Vargas T, Ugalde C, Spuch C, Antequera D, Mor\u00e1n MJ, Mart\u00edn MA, Ferrer I, Bermejo-Pareja F, Carro E. A\u03b2 accumulation in choroid plexus is associated with mitochondrial-induced apoptosis. Neurobiol Aging. 2010. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2008.08.017.","DOI":"10.1016\/j.neurobiolaging.2008.08.017"},{"issue":"4","key":"1849_CR50","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/ana.20624","volume":"58","author":"MF Beal","year":"2005","unstructured":"Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58(4):495\u2013505.","journal-title":"Ann Neurol"},{"key":"1849_CR51","doi-asserted-by":"publisher","unstructured":"Carro E, Vargas T, Antequera D, Ugalde C, Spuch C. Gelsolin restores A\u03b2 -induced alterations in choroid plexus epithelium. J Biomed Biotechnol. 2010. https:\/\/doi.org\/10.1155\/2010\/805405.","DOI":"10.1155\/2010\/805405"},{"key":"1849_CR52","doi-asserted-by":"publisher","unstructured":"Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, M\u00fcller-Spahn F, Haass C, Czech C, Pradier L, M\u00fcller WE, Eckert A. Amyloid \u03b2-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem. 2004. https:\/\/doi.org\/10.1074\/jbc.M405600200.","DOI":"10.1074\/jbc.M405600200"},{"key":"1849_CR53","doi-asserted-by":"publisher","unstructured":"Anthony SG, Schipper HM, Tavares R, Hovanesian V, Cortez SC, Stopa EG, Johanson CE. Stress protein expression in the Alzheimer-diseased choroid plexus. J Alzheimers Dis. 2003. https:\/\/doi.org\/10.3233\/JAD-2003-5301.","DOI":"10.3233\/JAD-2003-5301"},{"key":"1849_CR54","doi-asserted-by":"publisher","unstructured":"Schipper HM, Chertkow H, Mehindate K, Frankel D, Melmed C, Bergman H. Evaluation of heme oxygenase-1 as a systemic biological marker of sporadic AD. Neurology. 2000. https:\/\/doi.org\/10.1212\/WNL.54.6.1297.","DOI":"10.1212\/WNL.54.6.1297"},{"key":"1849_CR55","doi-asserted-by":"publisher","unstructured":"Perez-Gracia E, Blanco R, Carmona M, Carro E, Ferrer I. Oxidative stress damage and oxidative stress responses in the choroid plexus in Alzheimer\u2019s disease. Acta Neuropathol. 2009. https:\/\/doi.org\/10.1007\/s00401-009-0574-4.","DOI":"10.1007\/s00401-009-0574-4"},{"key":"1849_CR56","doi-asserted-by":"publisher","unstructured":"Meeker RB, Williams K, Killebrew DA, Hudson LC. Cell trafficking through the choroid plexus. Cell Adhes Migr. 2012. https:\/\/doi.org\/10.4161\/cam.21054.","DOI":"10.4161\/cam.21054"},{"key":"1849_CR57","doi-asserted-by":"publisher","unstructured":"Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science (80- ). 2014. https:\/\/doi.org\/10.1126\/science.1252945.","DOI":"10.1126\/science.1252945"},{"key":"1849_CR58","doi-asserted-by":"publisher","unstructured":"Dietrich MO, Spuch C, Antequera D, Rodal I, de Y\u00e9benes JG, Molina JA, Bermejo F, Carro E. Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging. 2008. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2007.01.008.","DOI":"10.1016\/j.neurobiolaging.2007.01.008"},{"key":"1849_CR59","doi-asserted-by":"publisher","unstructured":"Miklossy J, Kraftsik R, Pillevuit O, Lepori D, Genton C, Bosman FT. Curly fiber and tangle-like inclusions in the ependyma and choroid plexus - a pathogenetic relationship with the cortical Alzheimer-type changes? J Neuropathol Exp Neurol. 1998. https:\/\/doi.org\/10.1097\/00005072-199812000-00012.","DOI":"10.1097\/00005072-199812000-00012"},{"key":"1849_CR60","doi-asserted-by":"publisher","unstructured":"Miklossy J, Taddei K, Martins R, Escher G, Kraftsik R, Pillevuit O, Lepori D, Campiche M. Alzheimer disease: curly fibers and tangles in organs other than brain. J Neuropathol Exp Neurol. 1999. https:\/\/doi.org\/10.1097\/00005072-199908000-00003.","DOI":"10.1097\/00005072-199908000-00003"},{"key":"1849_CR61","doi-asserted-by":"publisher","unstructured":"R. R-C, J.W. H, A.A. R, R. V, A. B, E. J, R. F, K. A, A. H, S.H. Z. Choroid plexus acts as gatekeeper for TREM2, abnormal accumulation of ApoE, and fibrillary tau in Alzheimer\u2019s disease and in down syndrome dementia. J Alzheimer\u2019s Dis. 2019. doi: https:\/\/doi.org\/10.3233\/JAD-181179 LK - http:\/\/onesearch.unifi.it\/openurl\/39UFI\/39UFI_Services?&sid=EMBASE&issn=18758908&id=doi:10.3233%2FJAD-181179&atitle=Choroid+plexus+acts+as+gatekeeper+for+TREM2%2C+abnormal+accumulation+of+ApoE%2C+and+fibrillary+tau+in+Alzheimer%27s+disease+and+in+down+syndrome+dementia&stitle=J.+Alzheimer%27s+Dis.&title=Journal+of+Alzheimer%27s+Disease&volume=69&issue=1&spage=91&epage=109&aulast=Raha-Chowdhury&aufirst=Ruma&auinit=R.&aufull=Raha-Chowdhury+R.&coden=JADIF&isbn=&pages=91-109.","DOI":"10.3233\/JAD-181179"},{"key":"1849_CR62","doi-asserted-by":"publisher","unstructured":"Reusche E. Argyrophilic inclusions distinct from Alzheimer neurofibrillary changes in one case of dialysis-associated encephalopathy. Acta Neuropathol. 1997. https:\/\/doi.org\/10.1007\/s004010050757.","DOI":"10.1007\/s004010050757"},{"key":"1849_CR63","doi-asserted-by":"publisher","unstructured":"Wen GY, Wisniewski HM, Kascsak RJ. Biondi ring tangles in the choroid plexus of Alzheimer\u2019s disease and normal aging brains: a quantitative study. Brain Res. 1999. https:\/\/doi.org\/10.1016\/S0006-8993(99)01466-3.","DOI":"10.1016\/S0006-8993(99)01466-3"},{"key":"1849_CR64","doi-asserted-by":"publisher","unstructured":"Antequera D, Vargas T, Ugalde C, Spuch C, Molina JA, Ferrer I, Bermejo-Pareja F, Carro E. Cytoplasmic gelsolin increases mitochondrial activity and reduces A\u03b2 burden in a mouse model of Alzheimer\u2019s disease. Neurobiol Dis. 2009. https:\/\/doi.org\/10.1016\/j.nbd.2009.06.018.","DOI":"10.1016\/j.nbd.2009.06.018"},{"key":"1849_CR65","doi-asserted-by":"publisher","unstructured":"Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-\u03b2 levels. Nat Med. 2002. https:\/\/doi.org\/10.1038\/nm1202-793.","DOI":"10.1038\/nm1202-793"},{"key":"1849_CR66","doi-asserted-by":"publisher","unstructured":"Chauhan VPS, Ray I, Chauhan A, Wisniewski HM. Binding of gelsolin, a secretory protein, to amyloid \u03b2-protein. Biochem Biophys Res Commun. 1999. https:\/\/doi.org\/10.1006\/bbrc.1999.0623.","DOI":"10.1006\/bbrc.1999.0623"},{"key":"1849_CR67","doi-asserted-by":"publisher","unstructured":"Zlokovic BV, Martel CL, Matsubara E, Mccomb JG, Zheng G, Mccluskey RT, Frangione B, Ghiso J. Glycoprotein 330\/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid \u03b2 at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci U S A. 1996. https:\/\/doi.org\/10.1073\/pnas.93.9.4229.","DOI":"10.1073\/pnas.93.9.4229"},{"key":"1849_CR68","doi-asserted-by":"publisher","unstructured":"Sousa JC, Cardoso I, Marques F, Saraiva MJ, Palha JA. Transthyretin and Alzheimer\u2019s disease: where in the brain? Neurobiol Aging. 2007. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2006.03.015.","DOI":"10.1016\/j.neurobiolaging.2006.03.015"},{"key":"1849_CR69","doi-asserted-by":"publisher","unstructured":"Carro E, Trejo JL, Gerber A, Loetscher H, Torrado J, Metzger F, Torres-Aleman I. Therapeutic actions of insulin-like growth factor I on APP\/PS2 mice with severe brain amyloidosis. Neurobiol Aging. 2006. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2005.06.015.","DOI":"10.1016\/j.neurobiolaging.2005.06.015"},{"key":"1849_CR70","doi-asserted-by":"publisher","unstructured":"Kalaria RN, Premkumar DRD, Pax AB, Cohen DL, Lieberburg I. Production and increased detection of amyloid \u03b2 protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer\u2019s disease. Mol Brain Res. 1996. https:\/\/doi.org\/10.1016\/0169-328X(95)00180-Z.","DOI":"10.1016\/0169-328X(95)00180-Z"},{"key":"1849_CR71","volume-title":"Altered expression of amyloid \u03b2 precursor mRNAs in cerebral vessels, meninges, and choroid plexus in Alzheimer\u2019s disease. In: Annals of the New York Academy of Sciences","author":"DRD Premkumar","year":"1996","unstructured":"Premkumar DRD, Kalaria RN. Altered expression of amyloid \u03b2 precursor mRNAs in cerebral vessels, meninges, and choroid plexus in Alzheimer\u2019s disease. In: Annals of the New York Academy of Sciences; 1996."},{"key":"1849_CR72","doi-asserted-by":"publisher","unstructured":"Braak H, Del Tredici K. The pathological process underlying Alzheimer\u2019s disease in individuals under thirty. Acta Neuropathol. 2011. https:\/\/doi.org\/10.1007\/s00401-010-0789-4.","DOI":"10.1007\/s00401-010-0789-4"},{"key":"1849_CR73","doi-asserted-by":"publisher","unstructured":"Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer\u2019s disease. Brain. 2015. https:\/\/doi.org\/10.1093\/brain\/awv236.","DOI":"10.1093\/brain\/awv236"},{"key":"1849_CR74","doi-asserted-by":"publisher","unstructured":"Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL, Wisniewski T, Woltjer RL, Yamada M, Nelson PT. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014. https:\/\/doi.org\/10.1007\/s00401-014-1349-0.","DOI":"10.1007\/s00401-014-1349-0"},{"issue":"5","key":"1849_CR75","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s00401-015-1407-2","volume":"129","author":"KA Jellinger","year":"2015","unstructured":"Jellinger KA, Alafuzoff I, Attems J, Beach TG, Cairns NJ, Crary JF, Dickson DW, Hof PR, Hyman BT, Jack CR, Jicha GA, Knopman DS, Kovacs GG, Mackenzie IR, Masliah E, Montine TJ, Nelson PT, Schmitt F, Schneider JA, Serrano-Pozo A, Thal DR, Toledo JB, Trojanowski JQ, Troncoso JC, Vonsattel JP, Wisniewski T. PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 2015;129(5):757\u201362.","journal-title":"Acta Neuropathol"},{"key":"1849_CR76","doi-asserted-by":"publisher","first-page":"baz046","DOI":"10.1093\/database\/baz046","volume":"2019","author":"O Franz\u00e9n","year":"2019","unstructured":"Franz\u00e9n O, Gan L-M, Bj\u00f6rkegren JLM. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database. 2019;2019:baz046. https:\/\/doi.org\/10.1093\/database\/baz046.","journal-title":"Database"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01849-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12883-020-01849-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01849-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T23:41:28Z","timestamp":1630021288000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-020-01849-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,27]]},"references-count":76,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1849"],"URL":"https:\/\/doi.org\/10.1186\/s12883-020-01849-3","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,27]]},"assertion":[{"value":"18 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All research in this study was performed in accordance with the United States (US) National Institutions of Health guidelines for research involving human tissues. Brain tissue were obtained from the NIH NeuroBioBank at the Ican School of Medicine at Mount Sinai (New York, NY). Approval and permission to use human brain tissue for research was obtained from the NIH NeuroBioBank at the Ican School of Medicine at Mount Sinai in accordance with the institutional bioethics guidelines. All donors and their families gave written informed consent for autopsy and use of brain tissue for research purposes. As samples were obtained from deceased, de-identified, consenting individuals, no further ethical approval was required.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable as brain samples were collected post-mortem and de-identified.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"317"}}