{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:58:31Z","timestamp":1793833111464,"version":"4.6.1"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["15\/479"],"award-info":[{"award-number":["15\/479"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["16\/597"],"award-info":[{"award-number":["16\/597"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["21\/710"],"award-info":[{"award-number":["21\/710"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"publisher","award":["1846WF"],"award-info":[{"award-number":["1846WF"]}],"id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009477","name":"Lottery Health Research","doi-asserted-by":"publisher","award":["LHR-2020-127339"],"award-info":[{"award-number":["LHR-2020-127339"]}],"id":[{"id":"10.13039\/501100009477","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":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Introduction<\/jats:title>\n                <jats:p>Neutrophil accumulation is a well-established feature of Alzheimer\u2019s disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Materials and methods<\/jats:title>\n                <jats:p>We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP\/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>There was an increase in neutrophils in AD brains as well as in the murine APP\/PS1 model of AD. Indeed,  MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP\/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40478-022-01347-2","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T22:03:56Z","timestamp":1648159436000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":129,"title":["Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9861-3574","authenticated-orcid":false,"given":"Leon C. D.","family":"Smyth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"van Leeuwen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Highet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Magon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahyar","family":"Osanlouy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie N.","family":"Mathiesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Mockett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malvindar K.","family":"Singh-Bains","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa K.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Clarkson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice A.","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wickliffe C.","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L. M.","family":"Faull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Kettle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Dragunow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B.","family":"Hampton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"1347_CR1","doi-asserted-by":"crossref","unstructured":"Kolaczkowska E, Kubes P (2013) Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol, pp 159\u2013175","DOI":"10.1038\/nri3399"},{"key":"1347_CR2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nri.2017.10","volume":"17","author":"O Soehnlein","year":"2017","unstructured":"Soehnlein O, Steffens S, Hidalgo A, Weber C (2017) Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol 17:248\u2013261","journal-title":"Nat Rev Immunol"},{"key":"1347_CR3","doi-asserted-by":"crossref","unstructured":"Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL (2015) Alzheimer\u2019s disease. Nat Rev Dis Prim, pp 1\u201318","DOI":"10.1038\/nrdp.2015.56"},{"key":"1347_CR4","doi-asserted-by":"crossref","unstructured":"Swanson MEV, Scotter EL, Smyth LCD, Murray HC, Ryan B, Turner C, et al (2020) Identification of a dysfunctional microglial population in human Alzheimer\u2019s disease cortex using novel single-cell histology image analysis. Acta Neuropathol Commun, 8","DOI":"10.1186\/s40478-020-01047-9"},{"key":"1347_CR5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13024-018-0277-1","volume":"13","author":"J Rustenhoven","year":"2018","unstructured":"Rustenhoven J, Smith AM, Smyth LC, Jansson D, Scotter EL, Swanson MEV et al (2018) PU1 regulates Alzheimer\u2019s disease-associated genes in primary human microglia. Mol Neurodegener 13:44","journal-title":"Mol Neurodegener"},{"key":"1347_CR6","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell 169:1276-1290.e17","journal-title":"Cell"},{"key":"1347_CR7","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12974-018-1167-8","volume":"15","author":"LCD Smyth","year":"2018","unstructured":"Smyth LCD, Rustenhoven J, Park TI-H, Schweder P, Jansson D, Heppner PA et al (2018) Unique and shared inflammatory profiles of human brain endothelia and pericytes. J Neuroinflammat 15:138","journal-title":"J Neuroinflammat"},{"key":"1347_CR8","doi-asserted-by":"crossref","unstructured":"Rustenhoven J, Jansson D, Smyth LC, Dragunow M (2017) Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci 38","DOI":"10.1016\/j.tips.2016.12.001"},{"key":"1347_CR9","doi-asserted-by":"crossref","first-page":"990","DOI":"10.3389\/fnins.2019.00990","volume":"13","author":"R Volkman","year":"2019","unstructured":"Volkman R, Ben-Zur T, Kahana A, Garty BZ, Offen D (2019) Myeloperoxidase deficiency inhibits cognitive decline in the 5XFAD mouse model of Alzheimer\u2019s disease. Front Neurosci 13:990","journal-title":"Front Neurosci"},{"key":"1347_CR10","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.neurobiolaging.2014.01.003","volume":"35","author":"SH Baik","year":"2014","unstructured":"Baik SH, Cha M-Y, Hyun Y-M, Cho H, Hamza B, Kim DK et al (2014) Migration of neutrophils targeting amyloid plaques in Alzheimer\u2019s disease mouse model. Neurobiol Aging 35:1286\u20131292","journal-title":"Neurobiol Aging"},{"key":"1347_CR11","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nm.3913","volume":"21","author":"E Zenaro","year":"2015","unstructured":"Zenaro E, Pietronigro E, Bianca VD, Piacentino G, Marongiu L, Budui S et al (2015) Neutrophils promote Alzheimer\u2019s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21:880\u2013886","journal-title":"Nat Med"},{"key":"1347_CR12","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 et al (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":"1347_CR13","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X19873658","author":"O Bracko","year":"2019","unstructured":"Bracko O, Njiru BN, Swallow M, Ali M, Haft-Javaherian M, Schaffer CB (2019) Increasing cerebral blood flow improves cognition into late stages in Alzheimer\u2019s disease mice. J Cereb Blood Flow Metab. https:\/\/doi.org\/10.1177\/0271678X19873658","journal-title":"J Cereb Blood Flow Metab"},{"key":"1347_CR14","doi-asserted-by":"crossref","unstructured":"Smyth LCD, Rustenhoven J, Park TIH, Schweder P, Jansson D, Heppner PA, et al (2018) Unique and shared inflammatory profiles of human brain endothelia and pericytes. J Neuroinflammat 15","DOI":"10.1186\/s12974-018-1167-8"},{"key":"1347_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s42003-021-01787-x","volume":"4","author":"D Jansson","year":"2021","unstructured":"Jansson D, Dieriks VB, Rustenhoven J, Smyth LCD, Scotter E, Aalderink M et al (2021) Cardiac glycosides target barrier inflammation of the vasculature, meninges and choroid plexus. Commun Biol 4:1\u201317. https:\/\/doi.org\/10.1038\/s42003-021-01787-x","journal-title":"Commun Biol"},{"key":"1347_CR16","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/nm.2843","volume":"18","author":"EP Schmidt","year":"2012","unstructured":"Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L et al (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18:1217\u20131223","journal-title":"Nat Med"},{"key":"1347_CR17","doi-asserted-by":"crossref","unstructured":"Arts JJG, Mahlandt EK, Gr\u00f6nloh MLB, Schimmel L, Noordstra I, Gordon E, et al (2021) Endothelial junctional membrane protrusions serve as hotspots for neutrophil transmigration. eLife 10","DOI":"10.7554\/eLife.66074"},{"key":"1347_CR18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00441-017-2626-8","volume":"369","author":"S Gellhaar","year":"2017","unstructured":"Gellhaar S, Sunnemark D, Eriksson H, Olson L, Galter D (2017) Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson\u2019s and Alzheimer\u2019s disease. Cell Tissue Res 369:445\u2013454","journal-title":"Cell Tissue Res"},{"key":"1347_CR19","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/j.1471-4159.2004.02527.x","volume":"90","author":"PS Green","year":"2004","unstructured":"Green PS, Mendez AJ, Jacob JS, Crowley JR, Growdon W, Hyman BT et al (2004) Neuronal expression of myeloperoxidase is increased in Alzheimer\u2019s disease. J Neurochem 90:724\u2013733","journal-title":"J Neurochem"},{"key":"1347_CR20","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1074\/jbc.M807731200","volume":"284","author":"RA Maki","year":"2009","unstructured":"Maki RA, Tyurin VA, Lyon RC, Hamilton RL, Dekosky ST, Kagan VE et al (2009) Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease. J Biol Chem 284:3158\u20133169","journal-title":"J Biol Chem"},{"key":"1347_CR21","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1001\/archneur.61.3.341","volume":"61","author":"M Zappia","year":"2004","unstructured":"Zappia M, Manna I, Serra P, Cittadella R, Andreoli V, La Russa A et al (2004) Increased risk for Alzheimer disease with the Interaction of MPO and A2M polymorphisms. Arch Neurol 61:341\u2013344","journal-title":"Arch Neurol"},{"key":"1347_CR22","doi-asserted-by":"crossref","unstructured":"van Leeuwen E, Hampton MB, Smyth LCD (2020) Redox signalling and regulation of the blood-brain barrier. Int J Biochem Cell Biol","DOI":"10.1016\/j.biocel.2020.105794"},{"key":"1347_CR23","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1146\/annurev-biochem-060815-014442","volume":"85","author":"CC Winterbourn","year":"2016","unstructured":"Winterbourn CC, Kettle AJ, Hampton MB (2016) Reactive oxygen species and neutrophil function. Ann Rev Biochem 85:765\u2013792","journal-title":"Ann Rev Biochem"},{"key":"1347_CR24","doi-asserted-by":"crossref","unstructured":"Jorch SK, Kubes P (2017) An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med pp 279\u201387","DOI":"10.1038\/nm.4294"},{"key":"1347_CR25","doi-asserted-by":"crossref","unstructured":"Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathogens","DOI":"10.1371\/journal.ppat.1000639"},{"key":"1347_CR26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41590-019-0571-2","volume":"21","author":"JM Adrover","year":"2020","unstructured":"Adrover JM, Aroca-Crevill\u00e9n A, Crainiciuc G, Ostos F, Rojas-Vega Y, Rubio-Ponce A et al (2020) Programmed \u2018disarming\u2019 of the neutrophil proteome reduces the magnitude of inflammation. Nat Immunol 21:135\u2013144","journal-title":"Nat Immunol"},{"key":"1347_CR27","doi-asserted-by":"crossref","unstructured":"Tsourouktsoglou TD, Warnatsch A, Ioannou M, Hoving D, Wang Q, Papayannopoulos V (2020) Histones, DNA, and citrullination promote neutrophil extracellular trap inflammation by regulating the localization and activation of TLR4. Cell Rep 31","DOI":"10.1016\/j.celrep.2020.107602"},{"key":"1347_CR28","doi-asserted-by":"crossref","unstructured":"Papayannopoulos V (2018) Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, pp 134\u2013147","DOI":"10.1038\/nri.2017.105"},{"key":"1347_CR29","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1126\/science.aaa8064","volume":"349","author":"A Warnatsch","year":"2015","unstructured":"Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V (2015) Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349:316\u2013320","journal-title":"Science"},{"key":"1347_CR30","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.immuni.2019.07.002","volume":"51","author":"LE Mu\u00f1oz","year":"2019","unstructured":"Mu\u00f1oz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N et al (2019) Neutrophil extracellular traps initiate gallstone formation. Immunity 51:443-450.e4","journal-title":"Immunity"},{"key":"1347_CR31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jneumeth.2015.03.017","volume":"247","author":"PJ Narayan","year":"2015","unstructured":"Narayan PJ, Kim S-L, Lill C, Feng S, Faull RLM, Curtis MA et al (2015) Assessing fibrinogen extravasation into Alzheimer\u2019s disease brain using high-content screening of brain tissue microarrays. J Neurosci Methods 247:41\u201349","journal-title":"J Neurosci Methods"},{"key":"1347_CR32","doi-asserted-by":"publisher","first-page":"2308","DOI":"10.1038\/s41596-021-00503-7","volume":"16","author":"MK Singh-Bains","year":"2021","unstructured":"Singh-Bains MK, Mehrabi NF, Tan AYS, Faull RLM, Dragunow M (2021) Preparation, construction and high-throughput automated analysis of human brain tissue microarrays for neurodegenerative disease drug development. Nat Protoc 16:2308\u20132343. https:\/\/doi.org\/10.1038\/s41596-021-00503-7","journal-title":"Nat Protoc"},{"key":"1347_CR33","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nature09511","volume":"468","author":"AN Clarkson","year":"2010","unstructured":"Clarkson AN, Huang BS, MacIsaac SE, Mody I, Carmichael ST (2010) Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468:305\u2013309","journal-title":"Nature"},{"key":"1347_CR34","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/jcbfm.2013.7","volume":"33","author":"AN Clarkson","year":"2013","unstructured":"Clarkson AN, L\u00f3pez-Vald\u00e9s HE, Overman JJ, Charles AC, Brennan KC, Thomas CS (2013) Multimodal examination of structural and functional remapping in the mouse photothrombotic stroke model. J Cerebral Blood Flow Metabol 33:716\u2013723","journal-title":"J Cerebral Blood Flow Metabol"},{"key":"1347_CR35","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1177\/0271678X18755628","volume":"39","author":"AN Clarkson","year":"2019","unstructured":"Clarkson AN, Boothman-Burrell L, D\u00f3sa Z, Nagaraja RY, Jin L, Parker K et al (2019) The flavonoid, 2\u2032-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia. J Cereb Blood Flow Metab 39:1266\u20131282. https:\/\/doi.org\/10.1177\/0271678X18755628","journal-title":"J Cereb Blood Flow Metab"},{"key":"1347_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-21735-x","volume":"12","author":"D Maric","year":"2021","unstructured":"Maric D, Jahanipour J, Li XR, Singh A, Mobiny A, van Nguyen H et al (2021) Whole-brain tissue mapping toolkit using large-scale highly multiplexed immunofluorescence imaging and deep neural networks. Nat Commun 12:1\u201312. https:\/\/doi.org\/10.1038\/s41467-021-21735-x","journal-title":"Nat Commun"},{"key":"1347_CR37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s42003-022-03032-5","volume":"5","author":"HC Murray","year":"2022","unstructured":"Murray HC, Johnson K, Sedlock A, Highet B, Dieriks BV, Anekal PV et al (2022) Lamina-specific immunohistochemical signatures in the olfactory bulb of healthy, Alzheimer\u2019s and Parkinson\u2019s disease patients. Commun Biol 5:1\u201312","journal-title":"Commun Biol"},{"key":"1347_CR38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s40478-020-00986-7","volume":"8","author":"HC Murray","year":"2020","unstructured":"Murray HC, Dieriks BV, Swanson ME, Anekal PV, Turner C, Faull RLM et al (2020) The unfolded protein response is activated in the olfactory system in Alzheimer\u2019s disease. Acta Neuropathol Commun 8:109","journal-title":"Acta Neuropathol Commun"},{"key":"1347_CR39","doi-asserted-by":"crossref","unstructured":"Parker HA, Dickerhof N, Forrester L, Ryburn H, Smyth L, Messens J, et al (2021) Mycobacterium smegmatis resists the bactericidal activity of hypochlorous acid produced in neutrophil phagosomes. J Immunol ji2001084","DOI":"10.4049\/jimmunol.2001084"},{"key":"1347_CR40","doi-asserted-by":"crossref","unstructured":"Yang AC, Vest RT, Kern F, Lee DP, Agam M, Maat CA, et al (2022) A human brain vascular atlas reveals diverse mediators of Alzheimer\u2019s risk. Nature, pp 1\u20138","DOI":"10.1038\/s41586-021-04369-3"},{"key":"1347_CR41","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.4049\/jimmunol.1700834","volume":"200","author":"SJ Denstaedt","year":"2018","unstructured":"Denstaedt SJ, Spencer-Segal JL, Newstead MW, Laborc K, Zhao AP, Hjelmaas A et al (2018) S100A8\/A9 drives neuroinflammatory priming and protects against anxiety-like behavior after sepsis. J Immunol 200:3188\u20133200","journal-title":"J Immunol"},{"key":"1347_CR42","doi-asserted-by":"publisher","first-page":"8847","DOI":"10.1126\/sciadv.aax8847","volume":"6","author":"K Vaibhav","year":"2020","unstructured":"Vaibhav K, Braun M, Alverson K, Khodadadi H, Kutiyanawalla A, Ward A et al (2020) Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury. Sci Adv 6:8847. https:\/\/doi.org\/10.1126\/sciadv.aax8847","journal-title":"Sci Adv"},{"key":"1347_CR43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-13993-7","volume":"11","author":"L Kang","year":"2020","unstructured":"Kang L, Yu H, Yang X, Zhu Y, Bai X, Wang R et al (2020) Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke. Nat Commun 11:1\u201315","journal-title":"Nat Commun"},{"key":"1347_CR44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay5356","author":"F Binet","year":"2020","unstructured":"Binet F, Cagnone G, Crespo-Garcia S, Hata M, Neault M, Dejda A et al (2020) Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy. Science. https:\/\/doi.org\/10.1126\/science.aay5356","journal-title":"Science"},{"key":"1347_CR45","doi-asserted-by":"crossref","first-page":"18584","DOI":"10.1073\/pnas.0803945105","volume":"105","author":"MO Breckwoldt","year":"2008","unstructured":"Breckwoldt MO, Chen JW, Stangenberg L, Aikawa E, Rodriguez E, Qiu S et al (2008) Tracking the inflammatory response in stroke in vivo by se. Proc Natl Acad Sci USA 105:18584\u201318589","journal-title":"Proc Natl Acad Sci USA"},{"key":"1347_CR46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-48538-x","volume":"9","author":"E Pietronigro","year":"2019","unstructured":"Pietronigro E, Zenaro E, Bianca VD, Dusi S, Terrabuio E, Iannoto G et al (2019) Blockade of \u03b14 integrins reduces leukocyte\u2013endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer\u2019s disease. Sci Rep 9:1\u201315","journal-title":"Sci Rep"},{"key":"1347_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/0271678X221076568","volume":"41","author":"J-H Yoon","year":"2022","unstructured":"Yoon J-H, Shin P, Joo J, Kim GS, Oh W-Y, Jeong Y (2022) Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia. J Cereb Blood Flow Metab 41:1\u201315. https:\/\/doi.org\/10.1177\/0271678X221076568","journal-title":"J Cereb Blood Flow Metab"},{"key":"1347_CR48","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.3233\/JAD-141200","volume":"42","author":"K N\u00e4gga","year":"2014","unstructured":"N\u00e4gga K, Hansson O, van Westen D, Minthon L, Wennstr\u00f6m M (2014) Increased levels of hyaluronic acid in cerebrospinal fluid in patients with vascular dementia. J Alzheimer\u2019s Dis 42:1435\u20131441","journal-title":"J Alzheimer\u2019s Dis"},{"key":"1347_CR49","doi-asserted-by":"crossref","first-page":"257","DOI":"10.2174\/156720512800107537","volume":"9","author":"HM Nielsen","year":"2012","unstructured":"Nielsen HM, Palmqvist S, Minthon L, Londos E, Wennstrom M (2012) Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia. Curr Alzheimer Res 9:257\u2013266","journal-title":"Curr Alzheimer Res"},{"key":"1347_CR50","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1002\/ana.25159","volume":"83","author":"Y Dong","year":"2018","unstructured":"Dong Y, Lagarde J, Xicota L, Corne H, Chantran Y, Chaigneau T et al (2018) Neutrophil hyperactivation correlates with Alzheimer\u2019s disease progression. Ann Neurol 83:387\u2013405. https:\/\/doi.org\/10.1002\/ana.25159","journal-title":"Ann Neurol"},{"key":"1347_CR51","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1161\/ATVBAHA.118.311143","volume":"38","author":"K Manchanda","year":"2018","unstructured":"Manchanda K, Kolarova H, Kerkenpa\u00df C, Mollenhauer M, Vitecek J, Rudolph V et al (2018) MPO (myeloperoxidase) reduces endothelial glycocalyx thickness dependent on its cationic charge. Arterioscler Thromb Vasc Biol 38:1859\u20131867","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"1347_CR52","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.ajpath.2019.05.002","volume":"189","author":"K Suzuki","year":"2019","unstructured":"Suzuki K, Okada H, Takemura G, Takada C, Kuroda A, Yano H et al (2019) Neutrophil elastase damages the pulmonary endothelial glycocalyx in lipopolysaccharide-induced experimental endotoxemia. Am J Pathol 189:1526\u20131535","journal-title":"Am J Pathol"},{"key":"1347_CR53","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1161\/ATVBAHA.119.312725","volume":"39","author":"D Cheng","year":"2019","unstructured":"Cheng D, Talib J, Stanley CP, Rashid I, Micha\u00eblsson E, Lindstedt EL et al (2019) Inhibition of MPO (myeloperoxidase) attenuates endothelial dysfunction in mouse models of vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 39:1448\u20131457. https:\/\/doi.org\/10.1161\/ATVBAHA.119.312725","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"1347_CR54","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ijcard.2008.10.035","volume":"140","author":"TK Rudolph","year":"2010","unstructured":"Rudolph TK, Rudolph V, Witte A, Klinke A, Szoecs K, Lau D et al (2010) Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function. Int J Cardiol 140:42\u201347","journal-title":"Int J Cardiol"},{"key":"1347_CR55","doi-asserted-by":"crossref","unstructured":"\u00dcllen A, Singewald E, Konya V, Fauler G, Reicher H, Nusshold C, et al (2013) Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. PLoS ONE 8","DOI":"10.1371\/journal.pone.0064034"},{"key":"1347_CR56","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1042\/bj3270487","volume":"327","author":"CJ van Dalen","year":"1997","unstructured":"van Dalen CJ, Whitehouse MW, Winterbourn CC, Kettle AJ (1997) Thiocyanate and chloride as competing substrates for myeloperoxidase. Biochem J 327:487\u2013492","journal-title":"Biochem J"},{"key":"1347_CR57","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.freeradbiomed.2010.06.028","volume":"49","author":"SM Bozonet","year":"2010","unstructured":"Bozonet SM, Scott-Thomas AP, Nagy P, Vissers MCM (2010) Hypothiocyanous acid is a potent inhibitor of apoptosis and caspase 3 activation in endothelial cells. Free Radical Biol Med 49:1054\u20131063","journal-title":"Free Radical Biol Med"},{"key":"1347_CR58","doi-asserted-by":"publisher","unstructured":"Tilley DO, Abuabed U, Zimny-Arndt U, Schmid M, Florian S, Jungblut R, et al (2021) Histone H3 clipping is a novel signature of human neutrophil. bioRxiv. doi: https:\/\/doi.org\/10.1101\/2021.03.15.434949","DOI":"10.1101\/2021.03.15.434949"},{"key":"1347_CR59","doi-asserted-by":"crossref","unstructured":"van Leeuwen E, Hampton MB, Smyth LCD 2022 Hypothiocyanous Acid Disrupts the Barrier Function of Brain Endothelial Cells. Antioxidants 11 (in revision)","DOI":"10.3390\/antiox11040608"},{"key":"1347_CR60","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/jcbfm.2015.44","volume":"36","author":"MR Halliday","year":"2016","unstructured":"Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA et al (2016) Accelerated pericyte degeneration and blood\u2013brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer\u2019s disease. J Cereb Blood Flow Metab 36:216\u2013227. https:\/\/doi.org\/10.1038\/jcbfm.2015.44","journal-title":"J Cereb Blood Flow Metab"},{"key":"1347_CR61","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf7844","author":"A Cugurra","year":"2021","unstructured":"Cugurra A, Mamuladze T, Rustenhoven J, Dykstra T, Beroshvili G, Greenberg ZJ et al (2021) Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. https:\/\/doi.org\/10.1126\/science.abf7844","journal-title":"Science"},{"key":"1347_CR62","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1038\/s41593-018-0213-2","volume":"21","author":"F Herisson","year":"2018","unstructured":"Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K et al (2018) Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci 21:1209\u20131217","journal-title":"Nat Neurosci"},{"key":"1347_CR63","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s41591-019-0440-4","volume":"25","author":"H Yousef","year":"2019","unstructured":"Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA et al (2019) Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med 25:988\u20131000","journal-title":"Nat Med"},{"key":"1347_CR64","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1189\/jlb.0711387","volume":"91","author":"H Parker","year":"2012","unstructured":"Parker H, Albrett AM, Kettle AJ, Winterbourn CC (2012) Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide. J Leukoc Biol 91:369\u2013376. https:\/\/doi.org\/10.1189\/jlb.0711387","journal-title":"J Leukoc Biol"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-022-01347-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-022-01347-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-022-01347-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T12:09:32Z","timestamp":1648210172000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-022-01347-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,24]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["1347"],"URL":"https:\/\/doi.org\/10.1186\/s40478-022-01347-2","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,24]]},"assertion":[{"value":"9 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All human brain tissue protocols in this study were approved by the University of Auckland Human Participants Ethics Committee (2008\/279 and 011654), and all families provided informed consent. Venous blood was collected from healthy donors with informed consent under the ethical approval of the Southern Health and Disability Ethics Committee (Wellington, New Zealand [URA\/06\/12\/083]). Mice were obtained from the Biomedical Research Facility, University of Otago, New Zealand. All stroke procedures were performed in accordance with the guidelines on the care and use of laboratory animals set out by the University of Otago, Animal Research Committee (AUP-19\u2013160). Studies undertaken using these APP\/PS1 mice animals were approved by the University of Otago Animal Ethics Committee (AUP-19\u201382). All methods were carried out in accordance with the approved guidelines and New Zealand animal welfare legislation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38"}}