title: Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease.
abstract: There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitschelen
authors.affiliation: Department of Pathophysiology and Gerontology, Medical School and Szentágothai Research Center, University of Pecs, Hungary.
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia.
authors.forename: Gabor
authors.initials: G
authors.lastname: Szalai
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City. Department of Pathophysiology and Gerontology, Medical School and Szentágothai Research Center, University of Pecs, Hungary. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City. zoltan-ungvari@ouhsc.edu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City. Department of Pathophysiology and Gerontology, Medical School and Szentágothai Research Center, University of Pecs, Hungary. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
mesh_terms: D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001812:Blood-Brain Barrier; D002536:Cerebral Arteries / Q000502:physiology; D059305:Diet, High-Fat; D006624:Hippocampus / Q000378:metabolism*; D006706:Homeostasis; D007249:Inflammation / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress
chemical_list: D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases
keywords: Adipose; Alzheimer’s disease; Blood.; Insulin resistance; Metabolic syndrome