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 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.
Department of Physiology, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.
Trevor
T
Hardigan
Department of Pharmacology and Toxicology, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.|Department of Small Animal Behavior Core Facility, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.
Caterina
C
Hernandez
Department of Neuroscience, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.
Rebecca
R
Ward
Department of Medical Laboratory, Imaging and Radiologic Sciences, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.|Department of Neurology, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia.|Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia; and.
M Nasrul
MN
Hoda
Department of Physiology, University of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia; aergul@augusta.edu.|Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia.
Adviye
A
Ergul
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001522:Behavior, Animal; D002560:Cerebrovascular Circulation; D003071:Cognition; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior; D005239:Fear; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009473:Neuronal Plasticity; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D021641:Recognition, Psychology; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014665:Vasodilator Agents
Toll-like receptor 2; cerebral perfusion; cerebrovascular; cognitive impairment; diabetes