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

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.

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

“…Thus, the NRF2-knockout mouse shares many alterations common to AD patients or even aged individuals 156 . Recent studies have demonstrated that compared to wild-type animals, NRF2-knockout mice fed high-fat diet display greater neurovascular dysfunction, bloodbrain barrier disruption, neuroinflammation, amyloidogenic gene expression, and cognitive decline, mimicking many of the phenotypic changes that occur with aging 285 . The introduction of low NRF2 expression as a variable to reduce homeostatic responses may be useful to improve current models of chronic diseases towards better therapeutic outcomes.…”

Sodium butyrate protects against high-fat diet-induced oxidative stress in rat liver by promoting expression of nuclear factor E2-related factor 2

“…Nrf2 is a central regulator of oxidative stress that transactivates the expression of antioxidant proteins to protect against oxidative damage triggered by injury and inflammation (40) . A deficiency of Nrf2 exacerbates obesity-induced oxidative stress, neuroinflammation and cognitive decline in mice (41) . As a major nutraceutical component of green tea, epigallocatechin-3-gallate evokes Nrf2 nuclear translocation to ameliorate oxidative stress and insulin resistance in mice (42) .…”

Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

“…There is strong evidence that impairment of neurovascular coupling responses associates with cognitive decline (Tarantini et al 2015;Tarantini et al 2017c). Neurovascular coupling responses are sensitive to a wide range of cardiovascular risk factors (Tarantini et al 2019;Tarantini et al 2018a;Toth et al 2014Toth et al , 2015bTarantini et al 2017dTarantini et al , 2018bToth et al 2017;Tucsek et al 2014b), including changes in the hemodynamic environment (De Silva and Faraci 2012;Dunn and Nelson 2014;Faraco et al 2016;Kazama et al 2004). Thus, we Fig.…”