Circulating heparan sulfate fragments mediate septic cognitive dysfunction
Joseph A. Hippensteel, … , Paco S. Herson, Eric P. Schmidt
Joseph A. Hippensteel, … , Paco S. Herson, Eric P. Schmidt
Published February 5, 2019
Citation Information: J Clin Invest. 2019;129(4):1779-1784. https://doi.org/10.1172/JCI124485.
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Concise Communication Neuroscience

Circulating heparan sulfate fragments mediate septic cognitive dysfunction

Abstract

Septic 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.

Authors

Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Schmidt

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Figure 1

Cognitive impairment in mouse survivors of endotoxemia or sepsis is BDNF and TrkB responsive.

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Cognitive impairment in mouse survivors of endotoxemia or sepsis is BDNF...
(A) Memory impairment occurred in mice 7 days after i.p. administration of LPS (10 μg/g BW), as demonstrated by loss of freezing behavior (indicating a fearful memory of a previous paw shock) after contextual fear conditioning. (B) Living hippocampal slices isolated from mice 7 days after i.p. LPS administration (as compared with saline) showed impaired LTP, the BDNF-dependent neuronal process responsible for spatial memory. (C) A similar loss of LTP was also seen 7 days after CLP, a model of polymicrobial peritonitis–induced sepsis. Loss of LTP occurred 7 days after LPS, despite (D) maintenance of hippocampal BDNF content and (E) preserved responsiveness to excess (100 ng/ml) exogenous BDNF. (F) Maintenance of the BDNF-responsive molecular machinery of learning after sepsis was further demonstrated by reversal of memory deficits in post-LPS mice treated daily with 7,8-DHF (5 μg/g i.p.), a direct agonist of the BDNF receptor TrkB. *P < 0.05 and **P < 0.01, by t test. For LTP measurements, the left panels represent the mean ± SEM of groups; the right panels represent the average change from baseline over the final 10 minutes of measurement (each data point represents a unique biological replicate). TBS, theta burst stimulation.