TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits
The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is...
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| Veröffentlicht in: | American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2017-06, Vol.312 (6), p.R927-R937 |
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| container_title | American journal of physiology. Regulatory, integrative and comparative physiology |
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| creator | Hardigan, Trevor Hernandez, Caterina Ward, Rebecca Hoda, M Nasrul Ergul, Adviye |
| description | The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment. |
| doi_str_mv | 10.1152/ajpregu.00482.2016 |
| format | Article |
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The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.</description><identifier>ISSN: 0363-6119</identifier><identifier>EISSN: 1522-1490</identifier><identifier>DOI: 10.1152/ajpregu.00482.2016</identifier><identifier>PMID: 28336553</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Aorta - drug effects ; Aorta - physiopathology ; Behavior, Animal ; Blood flow ; Brain ; Cerebral blood flow ; Cerebrovascular Circulation ; Cerebrovascular system ; Chemokines ; Cognition ; Cognition & reasoning ; Cognition Disorders - genetics ; Cognition Disorders - metabolism ; Cognition Disorders - prevention & control ; Cognition Disorders - psychology ; Cognitive ability ; Cytokines ; Dementia disorders ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - metabolism ; Diabetic Angiopathies - genetics ; Diabetic Angiopathies - metabolism ; Diabetic Angiopathies - physiopathology ; Diabetic Angiopathies - prevention & control ; Dose-Response Relationship, Drug ; Endothelium ; Etiology ; Exploratory Behavior ; Fear ; Genetic Predisposition to Disease ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - physiopathology ; Immune system ; Impairment ; Inflammation ; Innate immunity ; Male ; Maze Learning ; Mice, Inbred C57BL ; Mice, Knockout ; Microvasculature ; Motor Activity ; Nephropathy ; Neuronal Plasticity ; Pathogenesis ; Perfusion ; Phenotype ; Prefrontal cortex ; Prefrontal Cortex - metabolism ; Prefrontal Cortex - physiopathology ; Recognition (Psychology) ; Time Factors ; TLR2 protein ; Toll-Like Receptor 2 - deficiency ; Toll-Like Receptor 2 - genetics ; Toll-like receptors ; Vascular diseases ; Vasodilation - drug effects ; Vasodilator Agents - pharmacology</subject><ispartof>American journal of physiology. 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Regulatory, integrative and comparative physiology</title><addtitle>Am J Physiol Regul Integr Comp Physiol</addtitle><description>The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.</description><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - physiopathology</subject><subject>Behavior, Animal</subject><subject>Blood flow</subject><subject>Brain</subject><subject>Cerebral blood flow</subject><subject>Cerebrovascular Circulation</subject><subject>Cerebrovascular system</subject><subject>Chemokines</subject><subject>Cognition</subject><subject>Cognition & reasoning</subject><subject>Cognition Disorders - genetics</subject><subject>Cognition Disorders - metabolism</subject><subject>Cognition Disorders - prevention & control</subject><subject>Cognition Disorders - psychology</subject><subject>Cognitive ability</subject><subject>Cytokines</subject><subject>Dementia disorders</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - genetics</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetic Angiopathies - genetics</subject><subject>Diabetic Angiopathies - metabolism</subject><subject>Diabetic Angiopathies - physiopathology</subject><subject>Diabetic Angiopathies - prevention & control</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endothelium</subject><subject>Etiology</subject><subject>Exploratory Behavior</subject><subject>Fear</subject><subject>Genetic Predisposition to Disease</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Hippocampus - physiopathology</subject><subject>Immune system</subject><subject>Impairment</subject><subject>Inflammation</subject><subject>Innate immunity</subject><subject>Male</subject><subject>Maze Learning</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microvasculature</subject><subject>Motor Activity</subject><subject>Nephropathy</subject><subject>Neuronal Plasticity</subject><subject>Pathogenesis</subject><subject>Perfusion</subject><subject>Phenotype</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - metabolism</subject><subject>Prefrontal Cortex - physiopathology</subject><subject>Recognition (Psychology)</subject><subject>Time Factors</subject><subject>TLR2 protein</subject><subject>Toll-Like Receptor 2 - deficiency</subject><subject>Toll-Like Receptor 2 - genetics</subject><subject>Toll-like receptors</subject><subject>Vascular diseases</subject><subject>Vasodilation - drug effects</subject><subject>Vasodilator Agents - pharmacology</subject><issn>0363-6119</issn><issn>1522-1490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU-LFDEQxYMo7uzqF_AgAS9eekzlT9u5CLKsrjAgyHoOmaS6N7MzSZukF_z2ZtxxUU9VUL96vMcj5BWwNYDi7-xuzjgta8bkwNecQf-ErNqBdyA1e0pWTPSi6wH0GTkvZccaKKR4Ts74IESvlFgRvNl84_QuJneXlkrnnCq6WqidbIilUh_sFiuW7oBtreipu7VxwkJDpA4zbrPd0xnzuJSQIrWxEWmKoYZ7pB7H4EItL8iz0e4LvjzNC_L909XN5XW3-fr5y-XHTeekYLVDKZST0nF8z61giE723joxsJbEi632Q--91DhosHLUI1coYHCggEv0XFyQDw-687Jthh3G2uyZOYeDzT9NssH8e4nh1kzp3iiplebQBN6eBHL6sWCp5hCKw_3eRkxLMTAMwHtQSjb0zX_oLi05tngGtOJMc9UfKf5AuZxKyTg-mgFmji2aU4vmd4vm2GJ7ev13jMeXP7WJXw6TnA0</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Hardigan, Trevor</creator><creator>Hernandez, Caterina</creator><creator>Ward, Rebecca</creator><creator>Hoda, M Nasrul</creator><creator>Ergul, Adviye</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TS</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170601</creationdate><title>TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits</title><author>Hardigan, Trevor ; Hernandez, Caterina ; Ward, Rebecca ; Hoda, M Nasrul ; Ergul, Adviye</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-e435c44c2e72a30eec46dac380036d3b9d86dd49e891a4f9f25e318c15124ed23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - physiopathology</topic><topic>Behavior, Animal</topic><topic>Blood flow</topic><topic>Brain</topic><topic>Cerebral blood flow</topic><topic>Cerebrovascular Circulation</topic><topic>Cerebrovascular system</topic><topic>Chemokines</topic><topic>Cognition</topic><topic>Cognition & reasoning</topic><topic>Cognition Disorders - genetics</topic><topic>Cognition Disorders - metabolism</topic><topic>Cognition Disorders - prevention & control</topic><topic>Cognition Disorders - psychology</topic><topic>Cognitive ability</topic><topic>Cytokines</topic><topic>Dementia disorders</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - genetics</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetic Angiopathies - genetics</topic><topic>Diabetic Angiopathies - metabolism</topic><topic>Diabetic Angiopathies - physiopathology</topic><topic>Diabetic Angiopathies - prevention & control</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endothelium</topic><topic>Etiology</topic><topic>Exploratory Behavior</topic><topic>Fear</topic><topic>Genetic Predisposition to Disease</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Hippocampus - physiopathology</topic><topic>Immune system</topic><topic>Impairment</topic><topic>Inflammation</topic><topic>Innate immunity</topic><topic>Male</topic><topic>Maze Learning</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microvasculature</topic><topic>Motor Activity</topic><topic>Nephropathy</topic><topic>Neuronal Plasticity</topic><topic>Pathogenesis</topic><topic>Perfusion</topic><topic>Phenotype</topic><topic>Prefrontal cortex</topic><topic>Prefrontal Cortex - metabolism</topic><topic>Prefrontal Cortex - physiopathology</topic><topic>Recognition (Psychology)</topic><topic>Time Factors</topic><topic>TLR2 protein</topic><topic>Toll-Like Receptor 2 - deficiency</topic><topic>Toll-Like Receptor 2 - genetics</topic><topic>Toll-like receptors</topic><topic>Vascular diseases</topic><topic>Vasodilation - drug effects</topic><topic>Vasodilator Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hardigan, Trevor</creatorcontrib><creatorcontrib>Hernandez, Caterina</creatorcontrib><creatorcontrib>Ward, Rebecca</creatorcontrib><creatorcontrib>Hoda, M Nasrul</creatorcontrib><creatorcontrib>Ergul, Adviye</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology. Regulatory, integrative and comparative physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hardigan, Trevor</au><au>Hernandez, Caterina</au><au>Ward, Rebecca</au><au>Hoda, M Nasrul</au><au>Ergul, Adviye</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits</atitle><jtitle>American journal of physiology. Regulatory, integrative and comparative physiology</jtitle><addtitle>Am J Physiol Regul Integr Comp Physiol</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>312</volume><issue>6</issue><spage>R927</spage><epage>R937</epage><pages>R927-R937</pages><issn>0363-6119</issn><eissn>1522-1490</eissn><abstract>The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>28336553</pmid><doi>10.1152/ajpregu.00482.2016</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Aorta - drug effects Aorta - physiopathology Behavior, Animal Blood flow Brain Cerebral blood flow Cerebrovascular Circulation Cerebrovascular system Chemokines Cognition Cognition & reasoning Cognition Disorders - genetics Cognition Disorders - metabolism Cognition Disorders - prevention & control Cognition Disorders - psychology Cognitive ability Cytokines Dementia disorders Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetic Angiopathies - genetics Diabetic Angiopathies - metabolism Diabetic Angiopathies - physiopathology Diabetic Angiopathies - prevention & control Dose-Response Relationship, Drug Endothelium Etiology Exploratory Behavior Fear Genetic Predisposition to Disease Hippocampus Hippocampus - metabolism Hippocampus - physiopathology Immune system Impairment Inflammation Innate immunity Male Maze Learning Mice, Inbred C57BL Mice, Knockout Microvasculature Motor Activity Nephropathy Neuronal Plasticity Pathogenesis Perfusion Phenotype Prefrontal cortex Prefrontal Cortex - metabolism Prefrontal Cortex - physiopathology Recognition (Psychology) Time Factors TLR2 protein Toll-Like Receptor 2 - deficiency Toll-Like Receptor 2 - genetics Toll-like receptors Vascular diseases Vasodilation - drug effects Vasodilator Agents - pharmacology |
| title | TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits |
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