{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:54:54Z","timestamp":1787018094173,"version":"build-2736575974"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,5]]},"abstract":"\n Background<\/jats:title>\n \n Heart failure (\n HF<\/jats:styled-content>\n ) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor\u2010\u03b1 (\n TNF\u2010<\/jats:styled-content>\n \u03b1)\u2013dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early\n HF<\/jats:styled-content>\n in which blood pressure remains minimally affected.\n HF<\/jats:styled-content>\n is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of\n cognitive impairments<\/jats:styled-content>\n in\n HF<\/jats:styled-content>\n is unknown, and appropriate treatment strategies are lacking.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We used a well\u2010established mouse model in which\n HF<\/jats:styled-content>\n was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size \u224825% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8\u00a0weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine\n TNF<\/jats:styled-content>\n \u2010\u03b1 during\n HF<\/jats:styled-content>\n \u2010mediated neuroinflammation and associated impaired hippocampus\u2010independent nonspatial episodic memory function. Augmented cerebral\n TNF<\/jats:styled-content>\n \u2010\u03b1 expression and microglial activation in\n HF<\/jats:styled-content>\n mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39\u00b18.61% for basal and 61.04\u00b19.18% for apical spines [\n P<\/jats:italic>\n <0.001]). The significance of\n TNF<\/jats:styled-content>\n \u2010\u03b1 signaling during the observed\n HF<\/jats:styled-content>\n \u2010mediated neurodegenerative processes is supported by evidence showing that sequestration or genetic deletion of\n TNF<\/jats:styled-content>\n \u2010\u03b1 ameliorates the observed reduction of cortical dendritic spines (33.51\u00b17.63% for basal and 30.13\u00b16.98% for apical spines in wild\u2010type mice treated with etanercept; 17.09\u00b16.81% for basal and 17.21\u00b17.29% for apical spines in\n TNF\u2010<\/jats:styled-content>\n \u03b1\n \u2212\/\u2212<\/jats:sup>\n ). Moreover, our data suggest that alterations in cerebral serum and glucocorticoid\u2010inducible kinase 1 (SgK1) expression and phosphorylation during\n HF<\/jats:styled-content>\n may be\n TNF<\/jats:styled-content>\n \u2010\u03b1 dependent and that an increase of SgK1 phosphorylation potentially plays a role in the\n HF<\/jats:styled-content>\n \u2010associated reduction of dendritic spine density.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings demonstrate that\n TNF<\/jats:styled-content>\n \u2010\u03b1 plays a pivotal role in\n HF<\/jats:styled-content>\n \u2010mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for\n HF<\/jats:styled-content>\n \u2010associated memory deficits.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.115.001920","type":"journal-article","created":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T22:10:56Z","timestamp":1430950256000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Tumor Necrosis Factor\u2010\u03b1 Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure"],"prefix":"10.1161","volume":"4","author":[{"given":"Anja","family":"Meissner","sequence":"first","affiliation":[{"name":"Department of Physiology University of Toronto Ontario Canada"},{"name":"Department of Brain Ischemia and Neurodegeneration Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi P.","family":"Visanji","sequence":"additional","affiliation":[{"name":"Morten and Gloria Shulman Movement Disorders Centre Toronto Western Hospital Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Abdul","family":"Momen","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Biology Toronto General Hospital Research Institute Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Feng","sequence":"additional","affiliation":[{"name":"Tanz Center for Research in Neurodegenerative Diseases Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly M.","family":"Francis","sequence":"additional","affiliation":[{"name":"Tanz Center for Research in Neurodegenerative Diseases Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen\u2010Sebastian","family":"Bolz","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Toronto Ontario Canada"},{"name":"Heart and Stroke\/Richard Lewar Centre of Excellence in Cardiovascular Research Toronto Ontario Canada"},{"name":"Toronto Centre for Microvascular Medicine 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