Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice

Zsuzsanna Tucsek, Peter Toth, Stefano Tarantini, Danuta Sosnowska, Tripti Gautam, Junie P. Warrington, Cory B. Giles, Jonathan D. Wren, Akos Koller, Praveen Ballabh, William E. Sonntag, Zoltan Ungvari, Anna Csiszar

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1339-1352
Number of pages14
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume69
Issue number11
DOIs
StatePublished - Aug 20 2014
Externally publishedYes

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Obesity
Microvessels
Blood-Brain Barrier
Cognition
Hippocampus
Cerebrovascular Circulation
Oxidative Stress
Cognitive Dysfunction
Vibrissae
Obese Mice
Pericytes
NADPH Oxidase
High Fat Diet
Inbred C57BL Mouse
Transcriptome
Amyloid
Epidemiologic Studies
Alzheimer Disease
Gene Expression
Brain

Keywords

  • Endothelial dysfunction
  • Learning and memory
  • MCI
  • Vascular cognitive impairment

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology
  • Medicine(all)

Cite this

Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. / Tucsek, Zsuzsanna; Toth, Peter; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Warrington, Junie P.; Giles, Cory B.; Wren, Jonathan D.; Koller, Akos; Ballabh, Praveen; Sonntag, William E.; Ungvari, Zoltan; Csiszar, Anna.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 69, No. 11, 20.08.2014, p. 1339-1352.

Research output: Contribution to journalArticle

Tucsek, Z, Toth, P, Tarantini, S, Sosnowska, D, Gautam, T, Warrington, JP, Giles, CB, Wren, JD, Koller, A, Ballabh, P, Sonntag, WE, Ungvari, Z & Csiszar, A 2014, 'Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 69, no. 11, pp. 1339-1352. https://doi.org/10.1093/gerona/glu080
Tucsek, Zsuzsanna ; Toth, Peter ; Tarantini, Stefano ; Sosnowska, Danuta ; Gautam, Tripti ; Warrington, Junie P. ; Giles, Cory B. ; Wren, Jonathan D. ; Koller, Akos ; Ballabh, Praveen ; Sonntag, William E. ; Ungvari, Zoltan ; Csiszar, Anna. / Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2014 ; Vol. 69, No. 11. pp. 1339-1352.
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N2 - 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.

AB - 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.

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