Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype

Stefano Tarantini, M. Noa Valcarcel-Ares, Andriy Yabluchanskiy, Zsuzsanna Tucsek, Peter Hertelendy, Tamas Kiss, Tripti Gautam, Xin A. Zhang, William E. Sonntag, Rafael De Cabo, E. Farkas, Michael H. Elliott, Michael T. Kinter, Ferenc Deak, Zoltan Ungvari, Anna Csiszar

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2 +/+ and Nrf2 -/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2 -/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Original languageEnglish
Pages (from-to)853-863
Number of pages11
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume73
Issue number7
DOIs
Publication statusPublished - Jun 14 2018

Fingerprint

Blood-Brain Barrier
Oxidative Stress
Obesity
Phenotype
Gene Expression
High Fat Diet
Cognitive Dysfunction
Long-Term Potentiation
Amyloid beta-Protein Precursor
Cell Aging
Health
Microglia
Transcriptome
Cognition
Blood Vessels
Hippocampus
Alzheimer Disease
Up-Regulation
Brain

Keywords

  • Endothelial dysfunction
  • Long-term potentiation
  • Vascular cognitive impairment
  • Vascular cognitive impairment
  • Vascular contributions to cognitive impairment and dementia

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Cite this

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype. / Tarantini, Stefano; Valcarcel-Ares, M. Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A.; Sonntag, William E.; De Cabo, Rafael; Farkas, E.; Elliott, Michael H.; Kinter, Michael T.; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 73, No. 7, 14.06.2018, p. 853-863.

Research output: Contribution to journalArticle

Tarantini, Stefano ; Valcarcel-Ares, M. Noa ; Yabluchanskiy, Andriy ; Tucsek, Zsuzsanna ; Hertelendy, Peter ; Kiss, Tamas ; Gautam, Tripti ; Zhang, Xin A. ; Sonntag, William E. ; De Cabo, Rafael ; Farkas, E. ; Elliott, Michael H. ; Kinter, Michael T. ; Deak, Ferenc ; Ungvari, Zoltan ; Csiszar, Anna. / Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2018 ; Vol. 73, No. 7. pp. 853-863.
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abstract = "Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2 +/+ and Nrf2 -/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2 -/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.",
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AU - Kiss, Tamas

AU - Gautam, Tripti

AU - Zhang, Xin A.

AU - Sonntag, William E.

AU - De Cabo, Rafael

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