title: Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice.
abstract: Epidemiological studies show 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 impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. 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. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. zoltan-ungvari@ouhsc.edu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. zoltan-ungvari@ouhsc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.affiliation: Oklahoma Medical Research Foundation, Arthritis and Clinical Immunology Research Program.
authors.forename: Cory B
authors.initials: CB
authors.lastname: Giles
authors.affiliation: Oklahoma Medical Research Foundation, Arthritis and Clinical Immunology Research Program.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
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: Departments of Pediatrics, Anatomy and Cell Biology, New York Medical College-Westchester Medical Center, Valhalla.
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Pathophysiology and Gerontology, Medical School and Szentágothai Research Center, University of Pecs, Hungary. Department of Physiology, University of Oklahoma Health Sciences Center. zoltan-ungvari@ouhsc.edu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center. Department of Pathophysiology and Gerontology, Medical School and Szentágothai Research Center, University of Pecs, Hungary. Department of Physiology, University of Oklahoma Health Sciences Center.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology* / Q000523:psychology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology / Q000523:psychology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018737:Hand Strength / Q000502:physiology; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D009765:Obesity / Q000150:complications* / Q000473:pathology / Q000523:psychology; D018384:Oxidative Stress; D020286:Pericytes / Q000473:pathology; D059467:Transcriptome
keywords: Endothelial dysfunction; Learning and memory.; MCI; Vascular cognitive impairment