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dc.contributor.authorHippensteel, Joseph A.
dc.contributor.authorAnderson, Brian J.
dc.contributor.authorOrfila, James E.
dc.contributor.authorMcMurtry, Sarah A.
dc.contributor.authorDietz, Robert M.
dc.contributor.authorSu, Guowei
dc.contributor.authorFord, Joshay A.
dc.contributor.authorOshima, Kaori
dc.contributor.authorYang, Yimu
dc.contributor.authorZhang, Fuming
dc.contributor.authorHan, Xiaorui
dc.contributor.authorYu, Yanlei
dc.contributor.authorLiu, Jian
dc.contributor.authorLinhardt, Robert J.
dc.contributor.authorMeyer, Nuala J.
dc.contributor.authorHerson, Paco S.
dc.contributor.authorSchmidt, Eric P.
dc.date2019
dc.date.accessioned2022-06-27T15:47:40Z
dc.date.available2022-06-27T15:47:40Z
dc.date.issued2019-01-01
dc.identifier.citationCirculating heparan sulfate fragments mediate septic cognitive dysfunction, J.A Hippensteel, B.J. Anderson, J. E. Orfila, S. A. McMurtry, R. Dietz, G. Su, J. A Ford, F. Zhang, J. Liu, R. J. Linhardt, N. J. Meyer, P. S. Herson, E. P. Schmidt, Journal of Clinical Investigation, 129, 1779-1784, 2019.
dc.identifier.issn15588238
dc.identifier.issn219738
dc.identifier.urihttps://doi.org/10.1172/JCI124485
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5551
dc.descriptionJournal of Clinical Investigation, 129, 1779-1784
dc.descriptionNote : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
dc.description.abstractSeptic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor-mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O- and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O- and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.
dc.description.sponsorshipNational Institutes of Health
dc.languageen_US
dc.language.isoENG
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofJournal of Clinical Investigation
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleCirculating heparan sulfate fragments mediate septic cognitive dysfunction
dc.typeArticle
dcterms.isPartOfJournal
dcterms.isVersionOfhttps://doi.org/10.1172/JCI124485
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
rpi.description.pages1779-1784
rpi.description.volume129


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