{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:49:20Z","timestamp":1792507760065,"version":"4.5.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,8,18]],"date-time":"2020-08-18T00:00:00Z","timestamp":1597708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,18]],"date-time":"2020-08-18T00:00:00Z","timestamp":1597708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["1K99AG061259"],"award-info":[{"award-number":["1K99AG061259"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["1RF1AG058674"],"award-info":[{"award-number":["1RF1AG058674"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P30AG062421"],"award-info":[{"award-number":["P30AG062421"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2016404F"],"award-info":[{"award-number":["A2016404F"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microangiopathy, including proliferation of small diameter capillaries, increasing vessel tortuosity, and increased capillary blockage by leukocytes, was previously observed in the aged rTg4510 mouse model. Similar gene expression changes related to angiogenesis were observed in both rTg4510 and Alzheimer\u2019s disease (AD). It is uncertain if tau is directly responsible for these vascular changes by interacting directly with microvessels, and\/or if it contributes indirectly via neurodegeneration and concurrent neuronal loss and inflammation. To better understand the nature of tau-related microangiopathy in human AD and in tau mice, we isolated capillaries and observed that bioactive soluble tau protein could be readily detected in association with vasculature. To examine whether this soluble tau is directly responsible for the microangiopathic changes, we made use of the tetracycline-repressible gene expression cassette in the rTg4510 mouse model and measured vascular pathology following tau reduction. These data suggest that reduction of tau is insufficient to alter established microvascular complications including morphological alterations, enhanced expression of inflammatory genes involved in leukocyte adherence, and blood brain barrier compromise. These data imply that 1) soluble bioactive tau surprisingly accumulates at the blood brain barrier in human brain and in mouse models, and 2) the morphological and molecular phenotype of microvascular disturbance does not resolve with reduction of whole brain soluble tau. Additional consideration of vascular-directed therapies and strategies that target tau in the vascular space may be required to restore normal function in neurodegenerative disease.<\/jats:p>","DOI":"10.1186\/s40478-020-01014-4","type":"journal-article","created":{"date-parts":[[2020,8,18]],"date-time":"2020-08-18T12:03:21Z","timestamp":1597752201000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Tau reduction in aged mice does not impact Microangiopathy"],"prefix":"10.1186","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9640-0575","authenticated-orcid":false,"given":"Rachel E.","family":"Bennett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Analiese","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Perez-Rando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Robbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarun","family":"Kamath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Dujardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,18]]},"reference":[{"key":"1014_CR1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3233\/JAD-2012-121336","volume":"33","author":"W Adriyani","year":"2013","unstructured":"Adriyani W, Ruzali W, Kehoe PG, Love S (2013) Influence of LRP-1 and Apolipoprotein E on amyloid-uptake and toxicity to cerebrovascular smooth muscle cells. J Alzheimers Dis 33:95\u2013110. https:\/\/doi.org\/10.3233\/JAD-2012-121336","journal-title":"J Alzheimers Dis"},{"key":"1014_CR2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s00401-013-1145-2","volume":"126","author":"M Arbel-Ornath","year":"2013","unstructured":"Arbel-Ornath M, Hudry E, Eikermann-Haerter K, Hou S, Gregory JL, Zhao L, Betensky RA, Frosch MP, Greenberg SM, Bacskai BJ (2013) Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer\u2019s disease mouse models. Acta Neuropathol 126:353\u2013364. https:\/\/doi.org\/10.1007\/s00401-013-1145-2","journal-title":"Acta Neuropathol"},{"key":"1014_CR3","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12916-014-0206-2","volume":"12","author":"J Attems","year":"2014","unstructured":"Attems J, Jellinger KA (2014) The overlap between vascular disease and Alzheimer\u2019s disease--lessons from pathology. BMC Med 12:206. https:\/\/doi.org\/10.1186\/s12916-014-0206-2","journal-title":"BMC Med"},{"key":"1014_CR4","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3389\/fnana.2017.00101","volume":"11","author":"A Bacyinski","year":"2017","unstructured":"Bacyinski A, Xu M, Wang W, Hu J (2017) The Paravascular pathway for brain waste clearance: current understanding, significance and controversy. Front Neuroanat 11:101. https:\/\/doi.org\/10.3389\/fnana.2017.00101","journal-title":"Front Neuroanat"},{"key":"1014_CR5","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1111\/dom.13538","volume":"21","author":"SC Bain","year":"2019","unstructured":"Bain SC, Klufas MA, Ho A, Matthews DR (2019) Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: a review. Diabetes Obes Metab 21:454\u2013466. https:\/\/doi.org\/10.1111\/dom.13538","journal-title":"Diabetes Obes Metab"},{"key":"1014_CR6","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 (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer\u2019s disease. Acta Neuropathol 118:103\u2013113. https:\/\/doi.org\/10.1007\/s00401-009-0522-3","journal-title":"Acta Neuropathol"},{"key":"1014_CR7","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1016\/J.AJPATH.2017.03.011","volume":"187","author":"RE Bennett","year":"2017","unstructured":"Bennett RE, DeVos SL, Dujardin S, Corjuc B, Gor R, Gonzalez J, Roe AD, Frosch MP, Pitstick R, Carlson GA, Hyman BT (2017) Enhanced tau aggregation in the presence of amyloid \u03b2. Am J Pathol 187:1601\u20131612. https:\/\/doi.org\/10.1016\/J.AJPATH.2017.03.011","journal-title":"Am J Pathol"},{"key":"1014_CR8","doi-asserted-by":"publisher","first-page":"E1289","DOI":"10.1073\/pnas.1710329115","volume":"115","author":"RE Bennett","year":"2018","unstructured":"Bennett RE, Robbins AB, Hu M, Cao X, Betensky RA, Clark T, Das S, Hyman BT (2018) Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer\u2019s disease. Proc Natl Acad Sci U S A 115:E1289\u2013E1298. https:\/\/doi.org\/10.1073\/pnas.1710329115","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1014_CR9","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.1212\/01.wnl.0000311445.21321.fc","volume":"70","author":"H Bian","year":"2008","unstructured":"Bian H, Van Swieten JC, Leight S, Massimo L, Wood E, Forman M, Moore P, De Koning I, Clark CM, Rosso S, Trojanowski J, Lee VMY, Grossman M (2008) CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 70:1827\u20131835. https:\/\/doi.org\/10.1212\/01.wnl.0000311445.21321.fc","journal-title":"Neurology"},{"key":"1014_CR10","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1007\/s00330-014-3172-3","volume":"24","author":"MAA Binnewijzend","year":"2014","unstructured":"Binnewijzend MAA, Kuijer JPA, van der Flier WM, Benedictus MR, M\u00f6ller CM, Pijnenburg YAL, Lemstra AW, Prins ND, Wattjes MP, van Berckel BNM, Scheltens P, Barkhof F (2014) Distinct perfusion patterns in Alzheimer\u2019s disease, frontotemporal dementia and dementia with Lewy bodies. Eur Radiol 24:2326\u20132333. https:\/\/doi.org\/10.1007\/s00330-014-3172-3","journal-title":"Eur Radiol"},{"key":"1014_CR11","doi-asserted-by":"publisher","first-page":"e23789","DOI":"10.1371\/journal.pone.0023789","volume":"6","author":"KE Biron","year":"2011","unstructured":"Biron KE, Dickstein DL, Gopaul R, Jefferies WA (2011) Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and Hypervascularity in Alzheimer\u2019s Disease. PLoS One 6:e23789. https:\/\/doi.org\/10.1371\/journal.pone.0023789","journal-title":"PLoS One"},{"key":"1014_CR12","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40478-015-0186-2","volume":"3","author":"LJ Blair","year":"2015","unstructured":"Blair LJ, Frauen HD, Zhang B, Nordhues BA, Bijan S, Lin YC, Zamudio F, Hernandez LD, Sabbagh JJ, Selenica ML, Dickey CA (2015) Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol Commun 3:8. https:\/\/doi.org\/10.1186\/s40478-015-0186-2","journal-title":"Acta Neuropathol Commun"},{"key":"1014_CR13","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1046\/j.1471-4159.1997.68051870.x","volume":"68","author":"EM Blanc","year":"1997","unstructured":"Blanc EM, Toborek M, Mark RJ, Hennig B, Mattson MP (1997) Amyloid beta-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells. J Neurochem 68:1870\u20131881","journal-title":"J Neurochem"},{"key":"1014_CR14","doi-asserted-by":"publisher","unstructured":"Boulay A-C, Saubam\u00e9a B, Decl\u00e8ves X, Cohen-Salmon M (2015) Purification of mouse brain vessels. J Vis Exp:e53208. https:\/\/doi.org\/10.3791\/53208","DOI":"10.3791\/53208"},{"key":"1014_CR15","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1212\/WNL.0000000000003655","volume":"88","author":"G Boulouis","year":"2017","unstructured":"Boulouis G, Charidimou A, Jessel MJ, Xiong L, Roongpiboonsopit D, Fotiadis P, Pasi M, Ayres A, Merrill ME, Schwab KM, Rosand J, Gurol ME, Greenberg SM, Viswanathan A (2017) Small vessel disease burden in cerebral amyloid angiopathy without symptomatic hemorrhage. Neurology 88:878\u2013884. https:\/\/doi.org\/10.1212\/WNL.0000000000003655","journal-title":"Neurology"},{"key":"1014_CR16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1093\/brain\/awf185","volume":"125","author":"KM Bradley","year":"2002","unstructured":"Bradley KM, O\u2019Sullivan VT, Soper NDW, Nagy Z, King EM-F, Smith AD, Shepstone BJ (2002) Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer\u2019s disease. Brain 125:1772\u20131781","journal-title":"Brain"},{"key":"1014_CR17","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41593-018-0289-8","volume":"22","author":"MA Busche","year":"2019","unstructured":"Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein N, Kamath TV, Carlson GA, Nelken I, Hyman BT (2019) Tau impairs neural circuits, dominating amyloid-\u03b2 effects, in Alzheimer models in vivo. Nat Neurosci 22:57\u201364. https:\/\/doi.org\/10.1038\/s41593-018-0289-8","journal-title":"Nat Neurosci"},{"key":"1014_CR18","doi-asserted-by":"publisher","first-page":"257","DOI":"10.14336\/AD.2017.0112","volume":"8","author":"DL Castillo-Carranza","year":"2017","unstructured":"Castillo-Carranza DL, Nilson AN, Van Skike CE, Jahrling JB, Patel K, Garach P, Gerson JE, Sengupta U, Abisambra J, Nelson P, Troncoso J, Ungvari Z, Galvan V, Kayed R (2017) Cerebral microvascular accumulation of tau oligomers in Alzheimer\u2019s Disease and related Tauopathies. Aging Dis 8:257\u2013266. https:\/\/doi.org\/10.14336\/AD.2017.0112","journal-title":"Aging Dis"},{"key":"1014_CR19","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2174\/157339907779802139","volume":"3","author":"R Chibber","year":"2007","unstructured":"Chibber R, Ben-Mahmud B, Chibber S, Kohner E (2007) Leukocytes in diabetic retinopathy. Curr Diabetes Rev 3:3\u201314. https:\/\/doi.org\/10.2174\/157339907779802139","journal-title":"Curr Diabetes Rev"},{"key":"1014_CR20","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s13195-015-0104-7","volume":"7","author":"HC Chui","year":"2015","unstructured":"Chui HC, Ramirez-Gomez L (2015) Clinical and imaging features of mixed Alzheimer and vascular pathologies. Alzheimers Res Ther 7:21. https:\/\/doi.org\/10.1186\/s13195-015-0104-7","journal-title":"Alzheimers Res Ther"},{"key":"1014_CR21","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41582-018-0013-z","volume":"14","author":"EE Congdon","year":"2018","unstructured":"Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14:399\u2013415. https:\/\/doi.org\/10.1038\/s41582-018-0013-z","journal-title":"Nat Rev Neurol"},{"key":"1014_CR22","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/s41593-018-0329-4","volume":"22","author":"JC Cruz Hern\u00e1ndez","year":"2019","unstructured":"Cruz Hern\u00e1ndez JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, Kang Y, Cortes-Canteli M, Peyrounette M, Doyeux V, Smith A, Zhou J, Otte G, Beverly JD, Davenport E, Davit Y, Lin CP, Strickland S, Iadecola C, Lorthois S, Nishimura N, Schaffer CB (2019) Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer\u2019s disease mouse models. Nat Neurosci 22:413\u2013420. https:\/\/doi.org\/10.1038\/s41593-018-0329-4","journal-title":"Nat Neurosci"},{"key":"1014_CR23","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.neuron.2011.11.033","volume":"73","author":"A de Calignon","year":"2012","unstructured":"de Calignon A, Polydoro M, Su\u00e1rez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer\u2019s Disease. Neuron 73:685\u2013697. https:\/\/doi.org\/10.1016\/j.neuron.2011.11.033","journal-title":"Neuron"},{"key":"1014_CR24","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/J.NICL.2016.08.001","volume":"12","author":"EGP Dopper","year":"2016","unstructured":"Dopper EGP, Chalos V, Ghariq E, den Heijer T, Hafkemeijer A, Jiskoot LC, de Koning I, Seelaar H, van Minkelen R, van Osch MJP, Rombouts SARB, van Swieten JC (2016) Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: a longitudinal arterial spin labeling study. Neuroimage Clin 12:460\u2013465. https:\/\/doi.org\/10.1016\/J.NICL.2016.08.001","journal-title":"Neuroimage Clin"},{"key":"1014_CR25","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.neurobiolaging.2016.11.004","volume":"50","author":"SF Eskildsen","year":"2017","unstructured":"Eskildsen SF, Gyldensted L, Nagenthiraja K, Nielsen RB, Hansen MB, Dalby RB, Frandsen J, Rodell A, Gyldensted C, Jespersen SN, Lund TE, Mouridsen K, Br\u00e6ndgaard H, \u00d8stergaard L (2017) Increased cortical capillary transit time heterogeneity in Alzheimer\u2019s disease: a DSC-MRI perfusion study. Neurobiol Aging 50:107\u2013118. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2016.11.004","journal-title":"Neurobiol Aging"},{"key":"1014_CR26","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1101\/gr.233866.117","volume":"29","author":"LO Goodwin","year":"2019","unstructured":"Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, Van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA (2019) Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res 29:494\u2013505. https:\/\/doi.org\/10.1101\/gr.233866.117","journal-title":"Genome Res"},{"key":"1014_CR27","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1126\/science.1062097","volume":"293","author":"J G\u00f6tz","year":"2001","unstructured":"G\u00f6tz J, Chen F, van Dorpe J, Nitsch RM, Lewis J, Gotz J, Chen F, Barmettler R, Nitsch RM, Gotz J, Gallyas F, Braak H, Braak E, Grundke-Iqbal I, Iqbal K, McKee AC, Kowall NW, Kosik KS, Velasco ME, Smith MA, Siedlak SL, Nunomura A, Perry G, Spillantini MG, Varadarajan S, Yatin S, Aksenova M, Butterfield DA, Lewis J, Price DL, Sisodia SS, Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW, Grundke-Iqbal I, Braak H, Braak E, Jicha GA, Bowser R, Kazam IG, Davies P, Goedert M, Dickson DW, Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I, Greenberg SG, Davies P, Schein JD, Binder LI, Goedert M, Jakes R, Vanmechelen E, Seubert P, Buee-Scherrer V, Delacourte A, Sergeant N, Wattez A, Gauvreau D, Robitaille Y, Sergeant N, Wattez A, Delacourte A, Gotz J, Probst A, Ehler E, Hemmings B, Kues W, Busciglio J, Lorenzo A, Yeh J, Yankner BA, Geula C, Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR, Hsiao KK, Probst A (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491\u20131495. https:\/\/doi.org\/10.1126\/science.1062097","journal-title":"Science"},{"key":"1014_CR28","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1742-2094-8-26","volume":"8","author":"P Grammas","year":"2011","unstructured":"Grammas P (2011) Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer\u2019s disease. J Neuroinflammation 8:26. https:\/\/doi.org\/10.1186\/1742-2094-8-26","journal-title":"J Neuroinflammation"},{"key":"1014_CR29","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1177\/08959374980120010301","volume":"12","author":"R Hanemaaijer","year":"1998","unstructured":"Hanemaaijer R, Visser H, Koolwijk P, Sorsa T, Salo T, Golub LM, van Hinsbergh VW (1998) Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res 12:114\u2013118. https:\/\/doi.org\/10.1177\/08959374980120010301","journal-title":"Adv Dent Res"},{"key":"1014_CR30","doi-asserted-by":"publisher","first-page":"180160","DOI":"10.1038\/sdata.2018.160","volume":"5","author":"L He","year":"2018","unstructured":"He L, Vanlandewijck M, M\u00e4e MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Lavi\u00f1a B, Gouveia L, Sun Y, Raschperger E, Segerstolpe \u00c5, Liu J, Gustafsson S, R\u00e4s\u00e4nen M, Zarb Y, Mochizuki N, Keller A, Lendahl U, Betsholtz C (2018) Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci Data 5:180160. https:\/\/doi.org\/10.1038\/sdata.2018.160","journal-title":"Sci Data"},{"key":"1014_CR31","doi-asserted-by":"publisher","first-page":"E4376","DOI":"10.1073\/pnas.1411649111","volume":"111","author":"BB Holmes","year":"2014","unstructured":"Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci 111:E4376\u2013E4385. https:\/\/doi.org\/10.1073\/pnas.1411649111","journal-title":"Proc Natl Acad Sci"},{"key":"1014_CR32","doi-asserted-by":"publisher","unstructured":"Hopp SC, Lin Y, Oakley D, Roe AD, Devos SL, Hanlon D, Hyman BT (2018) The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer\u2019s disease 11 medical and health sciences 1109 neurosciences. J Neuroinflammation. https:\/\/doi.org\/10.1186\/s12974-018-1309-z","DOI":"10.1186\/s12974-018-1309-z"},{"key":"1014_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","volume":"8","author":"BT Hyman","year":"2012","unstructured":"Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer\u2019s association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease. Alzheimers Dement 8:1\u201313. https:\/\/doi.org\/10.1016\/j.jalz.2011.10.007","journal-title":"Alzheimers Dement"},{"key":"1014_CR34","doi-asserted-by":"publisher","first-page":"16180","DOI":"10.1523\/JNEUROSCI.3020-14.2014","volume":"34","author":"JJ Iliff","year":"2014","unstructured":"Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R, Nedergaard M (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180\u201316193. https:\/\/doi.org\/10.1523\/JNEUROSCI.3020-14.2014","journal-title":"J Neurosci"},{"key":"1014_CR35","doi-asserted-by":"publisher","unstructured":"Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2. Sci Transl Med. https:\/\/doi.org\/10.1126\/scitranslmed.3003748","DOI":"10.1126\/scitranslmed.3003748"},{"key":"1014_CR36","doi-asserted-by":"publisher","first-page":"11934","DOI":"10.1038\/ncomms11934","volume":"7","author":"Y Iturria-Medina","year":"2016","unstructured":"Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-P\u00e9rez JM, Evans AC, Alzheimer\u2019s Disease Neuroimaging Initiative TADN (2016) Early role of vascular dysregulation on late-onset Alzheimer\u2019s disease based on multifactorial data-driven analysis. Nat Commun 7:11934. https:\/\/doi.org\/10.1038\/ncomms11934","journal-title":"Nat Commun"},{"key":"1014_CR37","doi-asserted-by":"publisher","first-page":"e867","DOI":"10.1212\/WNL.0000000000006082","volume":"91","author":"S Janelidze","year":"2018","unstructured":"Janelidze S, Mattsson N, Stomrud E, Lindberg O, Palmqvist S, Zetterberg H, Blennow K, Hansson O (2018) CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology 91:e867\u2013e877. https:\/\/doi.org\/10.1212\/WNL.0000000000006082","journal-title":"Neurology"},{"key":"1014_CR38","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1097\/00001756-199502000-00018","volume":"6","author":"RN Kalaria","year":"1995","unstructured":"Kalaria RN, Hedera P (1995) Differential degeneration of the cerebral microvasculature in Alzheimer\u2019s disease. Neuroreport 6:477\u2013480","journal-title":"Neuroreport"},{"key":"1014_CR39","doi-asserted-by":"publisher","first-page":"711","DOI":"10.3233\/JAD-161139","volume":"57","author":"HJ Kim","year":"2017","unstructured":"Kim HJ, Cho H, Werring DJ, Jang YK, Kim YJ, Lee JS, Lee J, Jun S, Park S, Ryu YH, Choi JY, Cho YS, Moon SH, Na DL, Lyoo CH, Seo SW (2017) 18F-AV-1451 PET imaging in three patients with probable cerebral amyloid Angiopathy. J Alzheimers Dis 57:711\u2013716. https:\/\/doi.org\/10.3233\/JAD-161139","journal-title":"J Alzheimers Dis"},{"key":"1014_CR40","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1001\/jamaneurol.2018.0975","volume":"75","author":"HJ Kim","year":"2018","unstructured":"Kim HJ, Park S, Cho H, Jang YK, San Lee J, Jang H, Kim Y, Kim KW, Ryu YH, Choi JY, Moon SH, Weiner MW, Jagust WJ, Rabinovici GD, DeCarli C, Lyoo CH, Na DL, Seo SW (2018) Assessment of extent and role of tau in subcortical vascular cognitive impairment using 18 F-AV1451 positron emission tomography imaging. JAMA Neurol 75:999. https:\/\/doi.org\/10.1001\/jamaneurol.2018.0975","journal-title":"JAMA Neurol"},{"key":"1014_CR41","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/10739680601131127","volume":"14","author":"C Kimura","year":"2007","unstructured":"Kimura C, Oike M, Watanabe M, Ito Y (2007) Proapoptotic nitric oxide production in amyloid \u03b2 protein-treated cerebral microvascular endothelial cells. Microcirculation 14:89\u201397. https:\/\/doi.org\/10.1080\/10739680601131127","journal-title":"Microcirculation"},{"key":"1014_CR42","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1126\/science.1058189","volume":"293","author":"J Lewis","year":"2001","unstructured":"Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E, Glenner GG, Wong CW, Masters CL, Wischik CM, Hardy J, Allsop D, Selkoe D, Roses AD, Goate A, Sherrington R, Levy-Lahad E, Scheuner D, Borchelt DR, Citron M, Mehta ND, Games D, Hsiao K, Duff K, Borchelt DR, Holcomb L, Lewis J, Hutton M, Lewis J, Mullan M, Lannfelt L, Jicha GA, Bowser R, Kazam IG, Davies P, Jicha GA, Mikol J, Brion S, Guicharnaud L, Waks O, Callahan MJ, Jorm AF, Korten AE, Henderson AS, Rocca WA, Gravina SA, Haugabook SJ, Greenberg SG, Davies P, Dickson DW, Vincent I, Zheng JH, Dickson DW, Kress Y, Davies P, Hardy J, Duff K, Gwinn-Hardy K, Perez-Tur J, Hutton M, G\u00f6tz J, Chen F, van Dorpe J, Nitsch RM (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487\u20131491. https:\/\/doi.org\/10.1126\/science.1058189","journal-title":"Science"},{"key":"1014_CR43","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1084\/jem.20172158","volume":"215","author":"H Martini-Stoica","year":"2018","unstructured":"Martini-Stoica H, Cole AL, Swartzlander DB, Chen F, Wan YW, Bajaj L, Bader DA, Lee VMY, Trojanowski JQ, Liu Z, Sardiello M, Zheng H (2018) TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med 215:2355\u20132377. https:\/\/doi.org\/10.1084\/jem.20172158","journal-title":"J Exp Med"},{"key":"1014_CR44","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s00401-016-1560-2","volume":"131","author":"M Merlini","year":"2016","unstructured":"Merlini M, Wanner D, Nitsch RM (2016) Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer\u2019s disease-related microvascular cerebral amyloid angiopathy. Acta Neuropathol 131:737\u2013752. https:\/\/doi.org\/10.1007\/s00401-016-1560-2","journal-title":"Acta Neuropathol"},{"key":"1014_CR45","doi-asserted-by":"publisher","first-page":"3587","DOI":"10.1073\/pnas.0709788105","volume":"105","author":"EP Meyer","year":"2008","unstructured":"Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T (2008) Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer\u2019s disease. Proc Natl Acad Sci U S A 105:3587\u20133592. https:\/\/doi.org\/10.1073\/pnas.0709788105","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1014_CR46","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1007\/BF00353892","volume":"269","author":"SK Moestrup","year":"1992","unstructured":"Moestrup SK, Gliemann J, Pallesen G (1992) Distribution of the \u03b12-macroglobulin receptor\/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 269:375\u2013382. https:\/\/doi.org\/10.1007\/BF00353892","journal-title":"Cell Tissue Res"},{"key":"1014_CR47","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.neuron.2014.12.032","volume":"85","author":"A Montagne","year":"2015","unstructured":"Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human Hippocampus. Neuron 85:296\u2013302. https:\/\/doi.org\/10.1016\/j.neuron.2014.12.032","journal-title":"Neuron"},{"key":"1014_CR48","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s00401-016-1570-0","volume":"131","author":"A Montagne","year":"2016","unstructured":"Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV (2016) Brain imaging of neurovascular dysfunction in Alzheimer\u2019s disease. Acta Neuropathol 131:687\u2013707. https:\/\/doi.org\/10.1007\/s00401-016-1570-0","journal-title":"Acta Neuropathol"},{"key":"1014_CR49","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1172\/JCI656","volume":"101","author":"M Morigi","year":"1998","unstructured":"Morigi M, Angioletti S, Imberti B, Donadelli R, Micheletti G, Figliuzzi M, Remuzzi A, Zoja C, Remuzzi G (1998) Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest 101:1905\u20131915. https:\/\/doi.org\/10.1172\/JCI656","journal-title":"J Clin Invest"},{"key":"1014_CR50","doi-asserted-by":"publisher","first-page":"390","DOI":"10.2967\/jnumed.107.045385","volume":"49","author":"L Mosconi","year":"2008","unstructured":"Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, Reiman EM, Holthoff V, Kalbe E, Sorbi S, Diehl-Schmid J, Perneczky R, Clerici F, Caselli R, Beuthien-Baumann B, Kurz A, Minoshima S, De Leon MJ (2008) Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer\u2019s disease, and other dementias. J Nucl Med 49:390\u2013398. https:\/\/doi.org\/10.2967\/jnumed.107.045385","journal-title":"J Nucl Med"},{"key":"1014_CR51","doi-asserted-by":"publisher","unstructured":"Narasimhan S, Changolkar L, Riddle DM, Kats A, Stieber A, Weitzman SA, Zhang B, Li Z, Roberson ED, Trojanowski JQ, Lee VMY (2020) Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J Exp Med. https:\/\/doi.org\/10.1084\/jem.20190783","DOI":"10.1084\/jem.20190783"},{"key":"1014_CR52","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","volume":"25","author":"DA Nation","year":"2019","unstructured":"Nation DA, Sweeney MD, Montagne A, Sagare AP, D\u2019Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV (2019) Blood\u2013brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270\u2013276. https:\/\/doi.org\/10.1038\/s41591-018-0297-y","journal-title":"Nat Med"},{"key":"1014_CR53","first-page":"403","volume":"1","author":"K Oshima","year":"2008","unstructured":"Oshima K, Uchikado H, Dickson DW (2008) Perivascular neuritic dystrophy associated with cerebral amyloid angiopathy in Alzheimer\u2019s disease. Int J Clin Exp Pathol 1:403\u2013408","journal-title":"Int J Clin Exp Pathol"},{"key":"1014_CR54","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13024-019-0312-x","volume":"14","author":"TK Patel","year":"2019","unstructured":"Patel TK, Habimana-Griffin L, Gao X, Xu B, Achilefu S, Alitalo K, McKee CA, Sheehan PW, Musiek ES, Xiong C, Coble D, Holtzman DM (2019) Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener 14:11. https:\/\/doi.org\/10.1186\/s13024-019-0312-x","journal-title":"Mol Neurodegener"},{"key":"1014_CR55","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40478-015-0199-x","volume":"3","author":"AM Pooler","year":"2015","unstructured":"Pooler AM, Polydoro M, Maury EA, Nicholls SB, Reddy SM, Wegmann S, William C, Saqran L, Cagsal-Getkin O, Pitstick R, Beier DR, Carlson GA, Spires-Jones TL, Hyman BT (2015) Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer\u2019s disease. Acta Neuropathol Commun 3:14. https:\/\/doi.org\/10.1186\/s40478-015-0199-x","journal-title":"Acta Neuropathol Commun"},{"key":"1014_CR56","doi-asserted-by":"publisher","first-page":"10637","DOI":"10.1523\/JNEUROSCI.3279-05.2005","volume":"25","author":"M Ramsden","year":"2005","unstructured":"Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, Hutton M, Ashe KH (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25:10637\u201310647. https:\/\/doi.org\/10.1523\/JNEUROSCI.3279-05.2005","journal-title":"J Neurosci"},{"key":"1014_CR57","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41586-020-2156-5","volume":"580","author":"JN Rauch","year":"2020","unstructured":"Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, Gradinaru V, Kampmann M, Kosik KS (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580:381\u2013385. https:\/\/doi.org\/10.1038\/s41586-020-2156-5","journal-title":"Nature"},{"key":"1014_CR58","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1111\/j.1582-4934.2008.00434.x","volume":"13","author":"JK Ryu","year":"2009","unstructured":"Ryu JK, McLarnon JG (2009) A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer\u2019s disease brain. J Cell Mol Med 13:2911\u20132925. https:\/\/doi.org\/10.1111\/j.1582-4934.2008.00434.x","journal-title":"J Cell Mol Med"},{"key":"1014_CR59","doi-asserted-by":"publisher","unstructured":"Sabbagh MF, Heng JS, Luo C, Castanon RG, Nery JR, Rattner A, Goff LA, Ecker JR, Nathans J (2018) Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. Elife. https:\/\/doi.org\/10.7554\/eLife.36187","DOI":"10.7554\/eLife.36187"},{"key":"1014_CR60","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1007\/s00401-016-1630-5","volume":"132","author":"E Sanchez-Mejias","year":"2016","unstructured":"Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nu\u00f1ez-Diaz C, Trujillo-Estrada L, Davila JC, Vizuete M, Gutierrez A, Vitorica J (2016) Soluble phospho-tau from Alzheimer\u2019s disease hippocampus drives microglial degeneration. Acta Neuropathol 132:897\u2013916. https:\/\/doi.org\/10.1007\/s00401-016-1630-5","journal-title":"Acta Neuropathol"},{"key":"1014_CR61","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1126\/science.1113694","volume":"309","author":"K Santacruz","year":"2005","unstructured":"Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476\u2013481. https:\/\/doi.org\/10.1126\/science.1113694","journal-title":"Science"},{"key":"1014_CR62","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1111\/j.1365-2990.2006.00736.x","volume":"32","author":"A-M Shiarli","year":"2006","unstructured":"Shiarli A-M, Jennings R, Shi J, Bailey K, Davidson Y, Tian J, Bigio EH, Ghetti B, Murrell JR, Delisle MB, Mirra S, Crain B, Zolo P, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, MacKenzie J, Khan N, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Mann DMA (2006) Comparison of extent of tau pathology in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with pick bodies and early onset Alzheimer\u2019s disease. Neuropathol Appl Neurobiol 32:374\u2013387. https:\/\/doi.org\/10.1111\/j.1365-2990.2006.00736.x","journal-title":"Neuropathol Appl Neurobiol"},{"key":"1014_CR63","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.2353\/ajpath.2006.050840","volume":"168","author":"TL Spires","year":"2006","unstructured":"Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of Tauopathy. Am J Pathol 168:1598\u20131607. https:\/\/doi.org\/10.2353\/ajpath.2006.050840","journal-title":"Am J Pathol"},{"key":"1014_CR64","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1007\/s00330-015-3789-x","volume":"26","author":"RME Steketee","year":"2016","unstructured":"Steketee RME, Bron EE, Meijboom R, Houston GC, Klein S, Mutsaerts HJMM, Mendez Orellana CP, de Jong FJ, van Swieten JC, van der Lugt A, Smits M (2016) Early-stage differentiation between presenile Alzheimer\u2019s disease and frontotemporal dementia using arterial spin labeling MRI. Eur Radiol 26:244\u2013253. https:\/\/doi.org\/10.1007\/s00330-015-3789-x","journal-title":"Eur Radiol"},{"key":"1014_CR65","first-page":"734","volume":"67","author":"PA Stewart","year":"1992","unstructured":"Stewart PA, Hayakawa K, Akers MA, Vinters HV (1992) A morphometric study of the blood-brain barrier in Alzheimer\u2019s disease. Lab Investig 67:734\u2013742","journal-title":"Lab Investig"},{"key":"1014_CR66","doi-asserted-by":"publisher","first-page":"8490","DOI":"10.1038\/ncomms9490","volume":"6","author":"S Takeda","year":"2015","unstructured":"Takeda S, Wegmann S, Cho H, DeVos SL, Commins C, Roe AD, Nicholls SB, Carlson GA, Pitstick R, Nobuhara CK, Costantino I, Frosch MP, M\u00fcller DJ, Irimia D, Hyman BT (2015) Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer\u2019s disease brain. Nat Commun 6:8490. https:\/\/doi.org\/10.1038\/ncomms9490","journal-title":"Nat Commun"},{"key":"1014_CR67","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1007\/s00702-014-1360-6","volume":"122","author":"DR Thal","year":"2015","unstructured":"Thal DR, von Arnim CAF, Griffin WST, Mrak RE, Walker L, Attems J, Arzberger T (2015) Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. J Neural Transm 122:1007\u20131018. https:\/\/doi.org\/10.1007\/s00702-014-1360-6","journal-title":"J Neural Transm"},{"key":"1014_CR68","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s00401-008-0366-2","volume":"115","author":"DR Thal","year":"2008","unstructured":"Thal DR, Griffin WST, de Vos RAI, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer\u2019s disease. Acta Neuropathol 115:599\u2013609. https:\/\/doi.org\/10.1007\/s00401-008-0366-2","journal-title":"Acta Neuropathol"},{"key":"1014_CR69","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/380168a0","volume":"380","author":"T Thomas","year":"1996","unstructured":"Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) \u03b2-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168\u2013171. https:\/\/doi.org\/10.1038\/380168a0","journal-title":"Nature"},{"key":"1014_CR70","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature25739","volume":"554","author":"M Vanlandewijck","year":"2018","unstructured":"Vanlandewijck M, He L, M\u00e4e MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Lavi\u00f1a B, Gouveia L, Sun Y, Raschperger E, R\u00e4s\u00e4nen M, Zarb Y, Mochizuki N, Keller A, Lendahl U, Betsholtz C (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:475\u2013480. https:\/\/doi.org\/10.1038\/nature25739","journal-title":"Nature"},{"key":"1014_CR71","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.neuron.2019.10.033","volume":"105","author":"SJ van Veluw","year":"2020","unstructured":"van Veluw SJ, Hou SS, Calvo-Rodriguez M, Arbel-Ornath M, Snyder AC, Frosch MP, Greenberg SM, Bacskai BJ (2020) Vasomotion as a driving force for Paravascular clearance in the awake mouse brain. Neuron 105:549\u2013561.e5. https:\/\/doi.org\/10.1016\/j.neuron.2019.10.033","journal-title":"Neuron"},{"key":"1014_CR72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s004010051186","volume":"100","author":"R Vidal","year":"2000","unstructured":"Vidal R, Calero M, Piccardo P, Farlow MR, Unverzagt FW, M\u00e9ndez E, Jim\u00e9nez-Huete A, Beavis R, Gallo G, Gomez-Tortosa E, Ghiso J, Hyman BT, Frangione B, Ghetti B (2000) Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele. Acta Neuropathol 100:1\u201312","journal-title":"Acta Neuropathol"},{"key":"1014_CR73","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.1242\/jcs.112.23.4347","volume":"112","author":"M Wachtel","year":"1999","unstructured":"Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM (1999) Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci 112:4347\u20134356","journal-title":"J Cell Sci"},{"key":"1014_CR74","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1111\/j.1365-2990.2005.00663.x","volume":"31","author":"S Williams","year":"2005","unstructured":"Williams S, Chalmers K, Wilcock GK, Love S (2005) Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer\u2019s disease. Neuropathol Appl Neurobiol 31:414\u2013421. https:\/\/doi.org\/10.1111\/j.1365-2990.2005.00663.x","journal-title":"Neuropathol Appl Neurobiol"},{"key":"1014_CR75","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1161\/CIRCULATIONAHA.117.027448","volume":"136","author":"FJ Wolters","year":"2017","unstructured":"Wolters FJ, Zonneveld HI, Hofman A, van der Lugt A, Koudstaal PJ, Vernooij MW, Ikram MA, Heart-Brain Connection Collaborative Research Group (2017) Cerebral perfusion and the risk of dementia: a population-based study. Circulation 136:719\u2013728. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.117.027448","journal-title":"Circulation"},{"key":"1014_CR76","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1093\/brain\/awz011","volume":"142","author":"Y Yamazaki","year":"2019","unstructured":"Yamazaki Y, Shinohara M, Shinohara M, Yamazaki A, Murray ME, Liesinger AM, Heckman MG, Lesser ER, Parisi JE, Petersen RC, Dickson DW, Kanekiyo T, Bu G (2019) Selective loss of cortical endothelial tight junction proteins during Alzheimer\u2019s disease progression. Brain 142:1077\u20131092. https:\/\/doi.org\/10.1093\/brain\/awz011","journal-title":"Brain"},{"key":"1014_CR77","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/sj.jcbfm.9600375","volume":"27","author":"Y Yang","year":"2007","unstructured":"Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697\u2013709. https:\/\/doi.org\/10.1038\/sj.jcbfm.9600375","journal-title":"J Cereb Blood Flow Metab"},{"key":"1014_CR78","doi-asserted-by":"publisher","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","volume":"34","author":"Y Zhang","year":"2014","unstructured":"Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O\u2019Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929\u201311947. https:\/\/doi.org\/10.1523\/JNEUROSCI.1860-14.2014","journal-title":"J Neurosci"},{"key":"1014_CR79","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neuron.2015.11.013","volume":"89","author":"Y Zhang","year":"2016","unstructured":"Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MSB, Li G, Duncan JA, Cheshier SH, Shuer LM, Chang EF, Grant GA, Gephart MGH, Barres BA (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37\u201353. https:\/\/doi.org\/10.1016\/j.neuron.2015.11.013","journal-title":"Neuron"},{"key":"1014_CR80","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/J.JNS.2008.05.020","volume":"272","author":"G Zuliani","year":"2008","unstructured":"Zuliani G, Cavalieri M, Galvani M, Passaro A, Munari MR, Bosi C, Zurlo A, Fellin R (2008) Markers of endothelial dysfunction in older subjects with late onset Alzheimer\u2019s disease or vascular dementia. J Neurol Sci 272:164\u2013170. https:\/\/doi.org\/10.1016\/J.JNS.2008.05.020","journal-title":"J Neurol Sci"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-01014-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-020-01014-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-01014-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T23:33:22Z","timestamp":1629243202000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-020-01014-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,18]]},"references-count":80,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1014"],"URL":"https:\/\/doi.org\/10.1186\/s40478-020-01014-4","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,18]]},"assertion":[{"value":"31 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures involving the use of human materials were performed in accordance with the ethical guidelines of the Partners Healthcare Institutional Review Board. The Institutional Animal Care Committee of Massachusetts General Hospital and McLaughlin Research Institute approved all animal study protocols.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors agreed to publish this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"137"}}