Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease

Sharma, Nidhi; Tramutola, Antonella; Lanzillotta, Chiara; Arena, Andrea; Blarzino, Carla; Cassano, Tommaso; Butterfield, D. Allan; Domenico, Fabio Di; Perluigi, Marzia; Barone, Eugenio

doi:10.1016/j.nbd.2019.02.003

Cited by 50 publications

(61 citation statements)

References 92 publications

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“…Thus, it is clear that BVRA can impact insulin signaling through its interactions with AKT. Others have shown that the loss of BVRA in the brain causes insulin-resistance that occurs in Alzheimer's disease [60][61][62]. However, the loss of BVRA in obesity can result in hyperactivation of insulin signaling [18].…”

Section: Discussionmentioning

confidence: 99%

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

et al. 2020

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Biliverdin reductase (BVR) is an enzymatic and signaling protein that has multifaceted roles in physiological systems. Despite the wealth of knowledge about BVR, no data exist regarding its actions in adipocytes. Here, we generated an adipose-specific deletion of biliverdin reductase-A (BVRA) (BlvraFatKO) in mice to determine the function of BVRA in adipocytes and how it may impact adipose tissue expansion. The BlvraFatKO and littermate control (BlvraFlox) mice were placed on a high-fat diet (HFD) for 12 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were quantitated at the end of the 12 weeks. The data showed that the percent body fat and body weights did not differ between the groups; however, BlvraFatKO mice had significantly higher visceral fat as compared to the BlvraFlox. The loss of adipocyte BVRA decreased the mitochondrial number in white adipose tissue (WAT), and increased inflammation and adipocyte size, but this was not observed in brown adipose tissue (BAT). There were genes significantly reduced in WAT that induce the browning effect such as Ppara and Adrb3, indicating that BVRA improves mitochondria function and beige-type white adipocytes. The BlvraFatKO mice also had significantly higher fasting blood glucose levels and no changes in plasma insulin levels, which is indicative of decreased insulin signaling in WAT, as evidenced by reduced levels of phosphorylated AKT (pAKT) and Glut4 mRNA. These results demonstrate the essential role of BVRA in WAT in insulin signaling and adipocyte hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

et al. 2020

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“…However, impairment of biliverdin reductase is a common clinical feature in the symptomatology of AD and type 2 diabetes mellitus (T2DM). These reports suggest that biliverdin reductase is important in the prevention of AD and T2DM [8,9,13]. Even though biliverdin reductase is involved in various diseases, the role of this enzyme in ischemic insults has not been investigated yet.…”

Section: Discussionmentioning

confidence: 99%

“…Biliverdin reductase and bilirubin are involved in various diseases, including brain damage and protection against oxidative stress-induced neuronal injury [6][7][8][9]. BLVRA has an antioxidant function on ROS via production of bilirubin.…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative stress-induced impairment of BLVRA increased accumulation of amyloid beta (Aβ) and tumor necrosis factor-alpha (TNF-α), that greatly contribute to the onset of brain insulin resistance along the progression of Alzheimer's disease pathology [11]. Similarly, reduced BLVRA levels increased oxidative stress and Tau phosphorylation in young triple transgenic AD (3xTg-AD)mice, suggesting loss of BLVRA impaired neuroprotection in response to oxidative stress in Alzheimer's disease (AD) [9]. In experimental autoimmune encephalomyelitis, biliverdin reductase more efficiently reduced clinical and pathological signs than treatments with other antioxidant enzymes in SH-SY5Y cells and in a Rat model [11].…”

Section: Introductionmentioning

confidence: 99%

“…In experimental autoimmune encephalomyelitis, biliverdin reductase more efficiently reduced clinical and pathological signs than treatments with other antioxidant enzymes in SH-SY5Y cells and in a Rat model [11]. In addition, biliverdin reductase and bilirubin are involved in the regulation of MAPK, phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt), and protein kinase C delta (PKCδ) signaling pathways and various gene expressions (growth regulators, differentiation factors, and transcription factors) related to cell survival, suggesting that biliverdin reductase may be a potential therapeutic agent for various diseases [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling

Kim

Shin

Kim

et al. 2020

IJMS

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Reactive oxygen species (ROS) is major risk factor in neuronal diseases including ischemia. Although biliverdin reductase A (BLVRA) plays a pivotal role in cell survival via its antioxidant function, its role in hippocampal neuronal (HT-22) cells and animal ischemic injury is not clearly understood yet. In this study, the effects of transducible fusion protein Tat-BLVRA on H2O2-induced HT-22 cell death and in an animal ischemia model were investigated. Transduced Tat-BLVRA markedly inhibited cell death, DNA fragmentation, and generation of ROS. Transduced Tat-BLVRA inhibited the apoptosis and mitogen activated protein kinase (MAPK) signaling pathway and it passed through the blood-brain barrier (BBB) and significantly prevented hippocampal cell death in an ischemic model. These results suggest that Tat-BLVRA provides a possibility as a therapeutic molecule for ischemia.

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Redox imbalance and metabolic defects in the context of Alzheimer disease

Di Domenico,

Lanzillotta,

Perluigi

2024

FEBS Letters

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Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration.

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Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease

Cited by 50 publications

References 92 publications

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling

Redox imbalance and metabolic defects in the context of Alzheimer disease

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