title: TLR4-dependent metabolic changes are associated with cognitive impairment in an animal model of type 1 diabetes.
abstract: We investigated the role of Toll-like receptor 4 (TLR4), a major mediator of innate immune responses, on cognitive performance in a type 1 diabetes model (T1D). After administration of streptozotocin, both TLR4 knockout (TLR4 KO) and wild type (WT) diabetic mice displayed metabolic alterations similar to those observed in T1D patients, including increased levels of glucose, cholesterol, triglycerides and ketones. T1D mice exhibited cognitive impairment which was less severe in TLR4 KO mice compared to WT mice. WT mice with higher glucose and those with higher triglyceride levels exhibited significantly more anxiety and impaired memory compared to those with lower levels of glucose and triglycerides; these correlations were absent in TLR4 KO mice. Additional findings suggest roles for TLR4 signaling in modifying the expression of enzymes involved in energy metabolism in brain cells in the setting of T1D. Our data show that TLR4 contributes to the negative impact of T1D on anxiety and cognition.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Kawamoto
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Rothman
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. Electronic address: camandolasi@mail.nih.gov.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013311:Streptozocin; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013311:Streptozocin
keywords: Anxiety; Diabetes; Ketones; Memory; TLR4