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J Gerontol A Biol Sci Med Sci. 2018 Jun 14;73(7):853-863. doi: 10.1093/gerona/glx177.

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.

Author information

1
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
2
Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.
3
Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Hungary.
4
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City.
5
Peggy & Charles Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City.
6
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
7
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City.
8
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City.
9
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City.
10
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City.
11
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City.

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.

PMID:
29905772
PMCID:
PMC6001893
[Available on 2019-06-14]
DOI:
10.1093/gerona/glx177

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