Sulforaphane inhibits the production of Aβ partially through activation of Nrf2-regulated Oxidative Stress

2021 ◽  
Author(s):  
Shunxi Zhang ◽  
Jia He Zhao ◽  
Zhihuai Bai ◽  
Fan Wu ◽  
Lina Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Potential Role ◽  
Regulation Mechanism ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Activator ◽  
Specific Symptoms

Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, presents a very potential role in improving the Alzheimer's disease (AD)-specific symptoms. However, the regulation mechanism of SFN...

scholarly journals Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2

2020 ◽  
Author(s):  
Yan Wang ◽  
Meiling Lian ◽  
Jing Zhou ◽  
shengzhou wu
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Luciferase Reporter ◽  
Cultured Neurons ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Dicer1 Expression

Abstract Background Oxidative stress critically underlies the neurodegenerative pathogenesis of Alzheimer's disease (AD). Depletion of Dicer1, an endoribonuclease central to microRNA maturation, also leads to neurodegeneration. We therefore hypothesized that altered Dicer1 expression may play a role in AD. Results Using immunoblotting and quantitative real-time PCR, we found that Dicer1 protein and mRNA levels were reduced in the hippocampi of animals of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-meditated Dicer1 knockdown induced oxidative stress, reduced mitochondrial intermembrane potential, and increased apoptosis in cultured neurons. Aβ42 exposure decreased Dicer1 and also down-regulated the oxidative stress–induced transcriptional regulator nuclear factor erythroid 2-related factor 2 (Nrf2). Conversely, Nrf2 overexpression increased Dicer1 mRNA and protein levels and reverted the Aβ42-induced Dicer1 reduction. To further investigate Dicer1 regulation, we cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Of note, injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. Conclusions These findings indicate that Dicer1 expression is reduced in the AD brain and that chronic Aβ exposure decreases Dicer1 levels in neurons via Nrf2–ARE signaling. Our results uncover a significant role for Dicer1 in AD and highlight that Dicer1 expression responds to oxidative stress in the brain.

scholarly journals Nrf2 Ablation Promotes Alzheimer’s Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Peng Ren ◽  
Jingwei Chen ◽  
Bingxuan Li ◽  
Mengzhou Zhang ◽  
Bei Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Related Factor ◽  
Qrt Pcr

Introduction. Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2. Methods. The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, Aβ, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR. Results. The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. Aβ and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Conclusion. Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.

scholarly journals Potential Role of Phenolic Extracts of Mentha in Managing Oxidative Stress and Alzheimer’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 631
Author(s):  
Doaa M. Hanafy ◽  
Geoffrey E. Burrows ◽  
Paul D. Prenzler ◽  
Rodney A. Hill
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Potential Role ◽  
The Elderly ◽  
Future Research ◽  
Phenolic Constituents ◽  
The Central Nervous System ◽  
Developed Nations

With an increase in the longevity and thus the proportion of the elderly, especially in developed nations, there is a rise in pathological conditions that accompany ageing, such as neurodegenerative disorders. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive and memory decline. The pathophysiology of the disease is poorly understood, with several factors contributing to its development, such as oxidative stress, neuroinflammation, cholinergic neuronal apoptotic death, and the accumulation of abnormal proteins in the brain. Current medications are only palliative and cannot stop or reverse the progression of the disease. Recent clinical trials of synthetic compounds for the treatment of AD have failed because of their adverse effects or lack of efficacy. Thus, there is impetus behind the search for drugs from natural origins, in addition to the discovery of novel, conventional therapeutics. Mints have been used traditionally for conditions relevant to the central nervous system. Recent studies showed that mint extracts and/or their phenolic constituents have a neuroprotective potential and can target multiple events of AD. In this review, we provide evidence of the potential role of mint extracts and their derivatives as possible sources of treatments in managing AD. Some of the molecular pathways implicated in the development of AD are reviewed, with focus on apoptosis and some redox pathways, pointing to mechanisms that may be modulated for the treatment of AD, and the need for future research invoking knowledge of these pathways is highlighted.

A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

2016 ◽  
Vol 130 (15) ◽  
pp. 1375-1387 ◽  
Author(s):  
Devy Deliyanti ◽  
Jae Young Lee ◽  
Steven Petratos ◽  
Colin J. Meyer ◽  
Keith W. Ward ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Capacity ◽  
Glial Cells ◽  
Related Factor ◽  
Nuclear Factor ◽  
Effective Strategy ◽  
Vascular Cell ◽  
Nrf2 Activator

A novel and potent nuclear factor erythroid-2 related factor 2 (Nrf2) activator, dh404, attenuates retinal vasculopathy by reducing oxidative stress-mediated damage to glia. Nrf2 agonists represent an effective strategy to improve vision-threatening glial and vascular cell pathology in ischaemic retinopathies.

scholarly journals Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Akira Uruno ◽  
Daisuke Matsumaru ◽  
Rie Ryoke ◽  
Ritsumi Saito ◽  
Shiori Kadoguchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Passive Avoidance ◽  
Cell Number ◽  
Passive Avoidance Task ◽  
Oxidative Stress Marker ◽  
Avoidance Task ◽  
Ionization Mass ◽  
Related Factor

ABSTRACT Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer’s disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF::Keap1FA/FA mice. Matrix-assisted laser desorption ionization–mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.

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