{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:08:28Z","timestamp":1790870908568,"version":"4.1.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T00:00:00Z","timestamp":1572220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T00:00:00Z","timestamp":1572220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["F31 MH113504"],"award-info":[{"award-number":["F31 MH113504"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["P01MH64570"],"award-info":[{"award-number":["P01MH64570"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["RO1 MH104147"],"award-info":[{"award-number":["RO1 MH104147"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RO1 AG057525"],"award-info":[{"award-number":["RO1 AG057525"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery. Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that can result in increased 1-year mortality when superimposed on dementia. Importantly, there are no disease-modifying therapeutic options for PND. Our lab developed the \u201cbroad spectrum\u201d mixed-lineage kinase 3 inhibitor URMC-099 to inhibit pathological innate immune responses that underlie neuroinflammation-associated cognitive dysfunction. Here, we test the hypothesis that URMC-099 can prevent surgery-induced neuroinflammation and cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Orthopedic surgery was performed by fracturing the tibia of the left hindlimb with intramedullary fixation under general anesthesia and analgesia. In a pilot experiment, 9-month-old mice were treated five times with URMC-099 (10\u2009mg\/kg, i.p.), spaced 12\u2009h apart, with three doses prior to surgery and two doses following surgery. In this experiment, microgliosis was evaluated using unbiased stereology and blood-brain barrier (BBB) permeability was assessed using immunoglobulin G (IgG) immunostaining. In follow-up experiments, 3-month-old mice were treated only three times with URMC-099 (10\u2009mg\/kg, i.p.), spaced 12\u2009h apart, prior to orthopedic surgery. Two-photon scanning laser microscopy and CLARITY with light-sheet microscopy were used to define surgery-induced changes in microglial dynamics and morphology, respectively. Surgery-induced memory impairment was assessed using the \u201cWhat-Where-When\u201d and Memory Load Object Discrimination tasks. The acute peripheral immune response to surgery was assessed by cytokine\/chemokine profiling and flow cytometry. Finally, long-term fracture healing was assessed in fracture callouses using micro-computerized tomography (microCT) and histomorphometry analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Orthopedic surgery induced BBB disruption and microglial activation, but had no effect on microglial process motility. Surgically treated mice exhibited impaired object place and identity discrimination in the \u201cWhat-Where-When\u201d and Memory Load Object Discrimination tasks. Both URMC-099 dosing paradigms prevented the neuroinflammatory sequelae that accompanied orthopedic surgery. URMC-099 prophylaxis had no effect on the mobilization of the peripheral innate immune response and fracture healing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings show that prophylactic URMC-099 treatment is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-019-1582-5","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T08:04:38Z","timestamp":1572249878000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders"],"prefix":"10.1186","volume":"16","author":[{"given":"Patrick","family":"Miller-Rhodes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuicui","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurpreet S.","family":"Baht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Saminathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona M.","family":"Rodriguiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Wetsel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris A.","family":"Gelbard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1803-5853","authenticated-orcid":false,"given":"Niccol\u00f2","family":"Terrando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,28]]},"reference":[{"issue":"5","key":"1582_CR1","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1111\/jgs.13406","volume":"63","author":"Ags\/Nia Delirium Conference Writing Group PC, Faculty","year":"2015","unstructured":"Ags\/Nia Delirium Conference Writing Group PC, Faculty. The American Geriatrics Society\/National Institute on Aging Bedside-to-Bench Conference: research agenda on delirium in older adults. J Am Geriatr Soc. 2015;63(5):843\u201352.","journal-title":"J Am Geriatr Soc"},{"issue":"5","key":"1582_CR2","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.bja.2017.11.087","volume":"121","author":"L Evered","year":"2018","unstructured":"Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018;121(5):1005\u201312.","journal-title":"Br J Anaesth"},{"issue":"3","key":"1582_CR3","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.jagp.2016.10.008","volume":"25","author":"HB Lee","year":"2017","unstructured":"Lee HB, Oldham MA, Sieber FE, Oh ES. Impact of delirium after hip fracture surgery on one-year mortality in patients with or without dementia: a case of effect modification. Am J Geriatr Psychiatry. 2017;25(3):308\u201315.","journal-title":"Am J Geriatr Psychiatry"},{"issue":"1","key":"1582_CR4","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1001\/archinternmed.2007.4","volume":"168","author":"DL Leslie","year":"2008","unstructured":"Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008;168(1):27\u201332.","journal-title":"Arch Intern Med"},{"key":"1582_CR5","doi-asserted-by":"crossref","unstructured":"Xiong C, Zhang Z, Baht GS, Terrando N. A mouse model of orthopedic surgery to study postoperative cognitive dysfunction and tissue regeneration. J Vis Exp. 2018;132.","DOI":"10.3791\/56701"},{"issue":"3","key":"1582_CR6","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/ana.22082","volume":"68","author":"M Cibelli","year":"2010","unstructured":"Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68(3):360\u20138.","journal-title":"Ann Neurol"},{"issue":"6","key":"1582_CR7","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1002\/ana.22664","volume":"70","author":"N Terrando","year":"2011","unstructured":"Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, et al. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70(6):986\u201395.","journal-title":"Ann Neurol"},{"key":"1582_CR8","doi-asserted-by":"publisher","first-page":"667","DOI":"10.2119\/molmed.2014.00143","volume":"20","author":"N Terrando","year":"2015","unstructured":"Terrando N, Yang T, Ryu JK, Newton PT, Monaco C, Feldmann M, et al. Stimulation of the alpha7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol Med. 2015;20:667\u201375.","journal-title":"Mol Med"},{"issue":"9","key":"1582_CR9","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.1096\/fj.13-230276","volume":"27","author":"N Terrando","year":"2013","unstructured":"Terrando N, Gomez-Galan M, Yang T, Carlstrom M, Gustavsson D, Harding RE, et al. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J. 2013;27(9):3564\u201371.","journal-title":"FASEB J"},{"issue":"7","key":"1582_CR10","doi-asserted-by":"publisher","first-page":"e91229","DOI":"10.1172\/jci.insight.91229","volume":"2","author":"X Feng","year":"2017","unstructured":"Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight. 2017;2(7):e91229.","journal-title":"JCI Insight"},{"issue":"47","key":"1582_CR11","doi-asserted-by":"publisher","first-page":"20518","DOI":"10.1073\/pnas.1014557107","volume":"107","author":"N Terrando","year":"2010","unstructured":"Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A. 2010;107(47):20518\u201322.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"43","key":"1582_CR12","doi-asserted-by":"publisher","first-page":"E6686","DOI":"10.1073\/pnas.1614017113","volume":"113","author":"MD Zhang","year":"2016","unstructured":"Zhang MD, Barde S, Yang T, Lei B, Eriksson LI, Mathew JP, et al. Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels. Proc Natl Acad Sci U S A. 2016;113(43):E6686\u2013E95.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"1582_CR13","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/ana.24909","volume":"81","author":"A Forsberg","year":"2017","unstructured":"Forsberg A, Cervenka S, Jonsson Fagerlund M, Rasmussen LS, Zetterberg H, Erlandsson Harris H, et al. The immune response of the human brain to abdominal surgery. Ann Neurol. 2017;81(4):572\u201382.","journal-title":"Ann Neurol"},{"issue":"24","key":"1582_CR14","doi-asserted-by":"publisher","first-page":"9998","DOI":"10.1523\/JNEUROSCI.0598-13.2013","volume":"33","author":"DF Marker","year":"2013","unstructured":"Marker DF, Tremblay M-\u00c8, Puccini JM, Barbieri J, Gantz Marker MA, Loweth CJ, et al. The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci. 2013;33(24):9998\u201310010.","journal-title":"J Neurosci"},{"issue":"1","key":"1582_CR15","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s12974-016-0646-z","volume":"13","author":"W Dong","year":"2016","unstructured":"Dong W, Embury CM, Lu Y, Whitmire SM, Dyavarshetty B, Gelbard HA, et al. The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-beta degradation. J Neuroinflammation. 2016;13(1):184.","journal-title":"J Neuroinflammation"},{"issue":"1","key":"1582_CR16","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s12974-018-1172-y","volume":"15","author":"T Kiyota","year":"2018","unstructured":"Kiyota T, Machhi J, Lu Y, Dyavarshetty B, Nemati M, Zhang G, et al. URMC-099 facilitates amyloid-beta clearance in a murine model of Alzheimer\u2019s disease. J Neuroinflammation. 2018;15(1):137.","journal-title":"J Neuroinflammation"},{"issue":"6","key":"1582_CR17","doi-asserted-by":"publisher","first-page":"ENEURO.0245-18.","DOI":"10.1523\/ENEURO.0245-18.2018","volume":"5","author":"Matthew J. Bellizzi","year":"2018","unstructured":"Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, et al. The mixed-lineage kinase inhibitor URMC-099 protects hippocampal synapses in experimental autoimmune encephalomyelitis. eNeuro. 2018;5(6).","journal-title":"eneuro"},{"issue":"20","key":"1582_CR18","doi-asserted-by":"publisher","first-page":"8032","DOI":"10.1021\/jm401094t","volume":"56","author":"VS Goodfellow","year":"2013","unstructured":"Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013;56(20):8032\u201348.","journal-title":"J Med Chem"},{"issue":"13","key":"1582_CR19","doi-asserted-by":"publisher","first-page":"5271","DOI":"10.1523\/JNEUROSCI.0650-14.2015","volume":"35","author":"JM Puccini","year":"2015","unstructured":"Puccini JM, Marker DF, Fitzgerald T, Barbieri J, Kim CS, Miller-Rhodes P, et al. Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders. J Neurosci. 2015;35(13):5271\u201383.","journal-title":"J Neurosci"},{"key":"1582_CR20","first-page":"103","volume":"10","author":"B Lei","year":"2013","unstructured":"Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation. 2013;10:103.","journal-title":"J Neuroinflammation"},{"key":"1582_CR21","doi-asserted-by":"crossref","unstructured":"Clark SD, Mikofsky R, Lawson J, Sulzer D. Piezo High Accuracy Surgical Osteal Removal (PHASOR): a technique for improved cranial window surgery in mice. J Vis Exp. 2018;133.","DOI":"10.3791\/56172"},{"issue":"2","key":"1582_CR22","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.neuron.2017.12.002","volume":"97","author":"C Madry","year":"2018","unstructured":"Madry C, Kyrargyri V, Arancibia-Carcamo IL, Jolivet R, Kohsaka S, Bryan RM, et al. Microglial ramification, surveillance, and interleukin-1beta release are regulated by the two-pore domain K(+) channel THIK-1. Neuron. 2018;97(2):299\u2013312 e6.","journal-title":"Neuron."},{"issue":"2","key":"1582_CR23","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.bbr.2009.09.014","volume":"215","author":"LM DeVito","year":"2010","unstructured":"DeVito LM, Eichenbaum H. Distinct contributions of the hippocampus and medial prefrontal cortex to the \u201cwhat-where-when\u201d components of episodic-like memory in mice. Behav Brain Res. 2010;215(2):318\u201325.","journal-title":"Behav Brain Res"},{"issue":"5","key":"1582_CR24","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1101\/lm.025213.111","volume":"19","author":"S Sannino","year":"2012","unstructured":"Sannino S, Russo F, Torromino G, Pendolino V, Calabresi P, De Leonibus E. Role of the dorsal hippocampus in object memory load. Learn Mem. 2012;19(5):211\u20138.","journal-title":"Learn Mem"},{"key":"1582_CR25","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.bone.2017.02.012","volume":"98","author":"GS Baht","year":"2017","unstructured":"Baht GS, Nadesan P, Silkstone D, Alman BA. Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair. Bone. 2017;98:31\u20136.","journal-title":"Bone."},{"issue":"4","key":"1582_CR26","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1002\/glia.23287","volume":"66","author":"I Paris","year":"2018","unstructured":"Paris I, Savage JC, Escobar L, Abiega O, Gagnon S, Hui CW, et al. ProMoIJ: a new tool for automatic three-dimensional analysis of microglial process motility. Glia. 2018;66(4):828\u201345.","journal-title":"Glia."},{"issue":"8","key":"1582_CR27","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1002\/glia.22686","volume":"62","author":"S Gyoneva","year":"2014","unstructured":"Gyoneva S, Davalos D, Biswas D, Swanger SA, Garnier-Amblard E, Loth F, et al. Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia. 2014;62(8):1345\u201360.","journal-title":"Glia."},{"issue":"24","key":"1582_CR28","doi-asserted-by":"publisher","first-page":"4930","DOI":"10.1182\/blood-2013-02-486217","volume":"121","author":"K De Filippo","year":"2013","unstructured":"De Filippo K, Dudeck A, Hasenberg M, Nye E, van Rooijen N, Hartmann K, et al. Mast cell and macrophage chemokines CXCL1\/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood. 2013;121(24):4930\u20137.","journal-title":"Blood."},{"issue":"4","key":"1582_CR29","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S1074-7613(02)00424-7","volume":"17","author":"CL Semerad","year":"2002","unstructured":"Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity. 2002;17(4):413\u201323.","journal-title":"Immunity."},{"issue":"9","key":"1582_CR30","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1017\/S1041610213000574","volume":"25","author":"J Witlox","year":"2013","unstructured":"Witlox J, Slor CJ, Jansen RW, Kalisvaart KJ, van Stijn MF, Houdijk AP, et al. The neuropsychological sequelae of delirium in elderly patients with hip fracture three months after hospital discharge. Int Psychogeriatr. 2013;25(9):1521\u201331.","journal-title":"Int Psychogeriatr"},{"issue":"1","key":"1582_CR31","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1186\/1742-2094-9-261","volume":"9","author":"DF Marker","year":"2012","unstructured":"Marker DF, Puccini JM, Mockus TE, Barbieri J, Lu S-M, Gelbard HA. LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein. J Neuroinflammation. 2012;9(1):261.","journal-title":"J Neuroinflammation"},{"issue":"2","key":"1582_CR32","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.yexmp.2010.05.009","volume":"89","author":"CA DeBoy","year":"2010","unstructured":"DeBoy CA, Rus H, Tegla C, Cudrici C, Jones MV, Pardo CA, et al. FLT-3 expression and function on microglia in multiple sclerosis. Exp Mol Pathol. 2010;89(2):109\u201316.","journal-title":"Exp Mol Pathol"},{"key":"1582_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nature17630","volume":"532","author":"L Fourgeaud","year":"2016","unstructured":"Fourgeaud L, Trav\u00e9s PG, Tufail Y, Leal-Bailey H, Lew ED, Burrola PG, et al. TAM receptors regulate multiple features of microglial physiology. Nature. 2016;532:1\u201315.","journal-title":"Nature."},{"key":"1582_CR34","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3389\/fimmu.2016.00441","volume":"7","author":"N Terrando","year":"2016","unstructured":"Terrando N, Yang T, Wang X, Fang J, Cao M, Andersson U, et al. Systemic HMGB1 neutralization prevents postoperative neurocognitive dysfunction in aged rats. Front Immunol. 2016;7:441.","journal-title":"Front Immunol"},{"issue":"8","key":"1582_CR35","doi-asserted-by":"publisher","first-page":"e0182471","DOI":"10.1371\/journal.pone.0182471","volume":"12","author":"Y Tang","year":"2017","unstructured":"Tang Y, Wang X, Zhang S, Duan S, Qing W, Chen G, et al. Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age. PLoS One. 2017;12(8):e0182471.","journal-title":"PLoS One"},{"issue":"7701","key":"1582_CR36","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s41586-018-0023-4","volume":"556","author":"AC Wendeln","year":"2018","unstructured":"Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556(7701):332\u20138.","journal-title":"Nature."},{"issue":"7751","key":"1582_CR37","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41586-019-1088-4","volume":"568","author":"JV Pluvinage","year":"2019","unstructured":"Pluvinage JV, Haney MS, Smith BAH, Sun J, Iram T, Bonanno L, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019;568(7751):187\u201392.","journal-title":"Nature."},{"key":"1582_CR38","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40478-015-0203-5","volume":"3","author":"IR Holtman","year":"2015","unstructured":"Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. 2015;3:31.","journal-title":"Acta Neuropathol Commun"},{"issue":"7","key":"1582_CR39","doi-asserted-by":"publisher","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. A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell. 2017;169(7):1276\u201390 e17.","journal-title":"Cell."},{"issue":"4","key":"1582_CR40","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/j.celrep.2019.03.099","volume":"27","author":"C Sala Frigerio","year":"2019","unstructured":"Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, et al. The major risk factors for Alzheimer\u2019s disease: age, sex, and genes modulate the microglia response to Abeta plaques. Cell Rep. 2019;27(4):1293\u2013306 e6.","journal-title":"Cell Rep"},{"issue":"7362","key":"1582_CR41","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nature10357","volume":"477","author":"SA Villeda","year":"2011","unstructured":"Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90\u20134.","journal-title":"Nature."},{"issue":"6","key":"1582_CR42","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/nm.3569","volume":"20","author":"SA Villeda","year":"2014","unstructured":"Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659\u201363.","journal-title":"Nat Med"},{"issue":"7651","key":"1582_CR43","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/nature22067","volume":"544","author":"JM Castellano","year":"2017","unstructured":"Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017;544(7651):488\u201392.","journal-title":"Nature."},{"issue":"6","key":"1582_CR44","doi-asserted-by":"publisher","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. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25(6):988\u20131000.","journal-title":"Nat Med"},{"issue":"6184","key":"1582_CR45","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1126\/science.1251141","volume":"344","author":"L Katsimpardi","year":"2014","unstructured":"Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630\u20134.","journal-title":"Science."},{"issue":"3","key":"1582_CR46","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.immuni.2019.02.012","volume":"50","author":"X Liu","year":"2019","unstructured":"Liu X, Nemeth DP, McKim DB, Zhu L, DiSabato DJ, Berdysz O, et al. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity. 2019;50(3):764\u20136.","journal-title":"Immunity."},{"key":"1582_CR47","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/1756-6606-4-27","volume":"4","author":"S Kondo","year":"2011","unstructured":"Kondo S, Kohsaka S, Okabe S. Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo. Mol Brain. 2011;4:27.","journal-title":"Mol Brain"},{"issue":"3","key":"1582_CR48","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1359\/jbmr.2002.17.3.513","volume":"17","author":"TJ Cho","year":"2002","unstructured":"Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res. 2002;17(3):513\u201320.","journal-title":"J Bone Miner Res"},{"issue":"3","key":"1582_CR49","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nrrheum.2012.1","volume":"8","author":"L Claes","year":"2012","unstructured":"Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133\u201343.","journal-title":"Nat Rev Rheumatol"},{"issue":"5","key":"1582_CR50","doi-asserted-by":"publisher","first-page":"547","DOI":"10.15252\/emmm.201404487","volume":"7","author":"JK Chan","year":"2015","unstructured":"Chan JK, Glass GE, Ersek A, Freidin A, Williams GA, Gowers K, et al. Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Mol Med. 2015;7(5):547\u201361.","journal-title":"EMBO Mol Med"},{"issue":"3","key":"1582_CR51","doi-asserted-by":"publisher","first-page":"3078","DOI":"10.1002\/jcp.27128","volume":"234","author":"JL Ramirez-Garcia-Luna","year":"2019","unstructured":"Ramirez-Garcia-Luna JL, Wong TH, Chan D, Al-Saran Y, Awlia A, Abou-Rjeili M, et al. Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation. J Cell Physiol. 2019;234(3):3078\u201387.","journal-title":"J Cell Physiol"},{"issue":"11","key":"1582_CR52","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1172\/JCI59041","volume":"121","author":"W Zou","year":"2011","unstructured":"Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, et al. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest. 2011;121(11):4383\u201392.","journal-title":"J Clin Invest"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1582-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12974-019-1582-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1582-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T20:19:28Z","timestamp":1603743568000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-019-1582-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,28]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1582"],"URL":"https:\/\/doi.org\/10.1186\/s12974-019-1582-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/537472","asserted-by":"object"}]},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,28]]},"assertion":[{"value":"2 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal procedures were carried out under protocols approved by the Duke University Medical Center and University of Rochester Medical Center, Institutional Animal Care and Use Committee under the National Research Council Guide for the Care and Use of Laboratory Animals, 8th edition. Both Duke University and University of Rochester Medical Center are AAALAC-accredited institutions.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read the manuscript and consent to its publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"URMC-099 is owned by URMC (HA Gelbard. lead inventor: patent nos. US 8,846,909 B2; 8,877,772; and 9,181,247 and associated international patents). HAG has no commercial disclosures regarding URMC-099 at present.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"193"}}