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Antioxidants
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Role of NRF2 Pathway in Neurodegenerative Diseases
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Role of NRF2 Pathway in Neurodegenerative Diseases

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (19 December 2024) | Viewed by 10074

Special Issue Editor

Dr. Isabel Lastres-Becker

E-Mail Website
Guest Editor
1. Instituto de Investigaciones Biomédicas “Sols-Moreale” UAM-CSIC, c/Arturo Duperier 4, 28029 Madrid, Spain
2. Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, 28040 Madrid, Spain
3. Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, 28029 Madrid, Spain
4. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain
Interests: neurodegenerative diseases; NRF2; oxidative stress; neuroinflammation; RNA-binding proteins; mitochondria
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although the trigger of the neurodegenerative disease process is unknown, the relevance of aging stands out as a major risk for the development of neurodegeneration. With age, a multitude of changes occur at the molecular level, such as an increase in oxidative stress and a decrease in the antioxidant capacity of an organism, with the decrease in the levels of the transcription factor NRF2 being one of the main causes of this imbalance. This creates a favorable environment for the development of neurodegenerative diseases. Although each of these diseases has its own characteristics, they all share altered proteostasis, oxidative stress and neuroinflammation. In recent years, it has been described that the transcription factor NRF2 is involved in the modulation of all these processes, becoming a pleiotropic factor. Therefore, understanding the involvement of NRF2 in the different mechanisms associated with neurodegeneration may be of vital importance in establishing new therapeutic targets.

As Guest Editor, I invite you to contribute to this Special Issue, whose focus will be the role of NRF2 in neurodegenerative disorders.

We also invite researchers in the field and the participants of the COST Action CA20121, Bench to Bedside Transition for Pharmacological regulation of NRF2 in non-communicable diseases (BenBedPhar), to submit their latest research findings to this Special Issue. We look forward to reading your contributions.

Dr. Isabel Lastres-Becker
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • Down syndrome
  • frontotemporal dementia
  • Parkinson’s disease
  • Huntington’s disease
  • amyotrophic lateral sclerosis
  • ischemia
  • oxidative stress
  • neuroinflammation
  • proteostasis
  • mitochondria

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Published Papers (5 papers)

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Research

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17 pages, 3351 KiB  
Article
Beneficial Effect of Dimethyl Fumarate Drug Repositioning in a Mouse Model of TDP-43-Dependent Frontotemporal Dementia
by Ignacio Silva-Llanes, Raquel Martín-Baquero, Alicia Berrojo-Armisen, Carmen Rodríguez-Cueto, Javier Fernández-Ruiz, Eva De Lago and Isabel Lastres-Becker
Antioxidants 2024, 13(9), 1072; https://doi.org/10.3390/antiox13091072 - 2 Sep 2024
Cited by 1 | Viewed by 2014
Abstract
Frontotemporal dementia (FTD) causes progressive neurodegeneration in the frontal and temporal lobes, leading to behavioral, cognitive, and language impairments. With no effective treatment available, exploring new therapeutic approaches is critical. Recent research highlights the transcription factor Nuclear Factor erythroid-derived 2-like 2 (NRF2) as [...] Read more.
Frontotemporal dementia (FTD) causes progressive neurodegeneration in the frontal and temporal lobes, leading to behavioral, cognitive, and language impairments. With no effective treatment available, exploring new therapeutic approaches is critical. Recent research highlights the transcription factor Nuclear Factor erythroid-derived 2-like 2 (NRF2) as vital in limiting neurodegeneration, with its activation shown to mitigate FTD-related processes like inflammation. Dimethyl fumarate (DMF), an NRF2 activator, has demonstrated neuroprotective effects in a TAU-dependent FTD mouse model, reducing neurodegeneration and inflammation. This suggests DMF repositioning potential for FTD treatment. Until now, no trial had been conducted to analyze the effect of DMF on TDP-43-dependent FTD. In this study, we aimed to determine the potential therapeutic efficacy of DMF in a TDP-43-related FTD mouse model that exhibits early cognitive impairment. Mice received oral DMF treatment every other day from presymptomatic to symptomatic stages. By post-natal day (PND) 60, an improvement in cognitive function is already evident, becoming even more pronounced by PND90. This cognitive enhancement correlates with the neuroprotection observed in the dentate gyrus and a reduction in astrogliosis in the stratum lacunosum-moleculare zone. At the prefrontal cortex (PFC) level, a neuroprotective effect of DMF is also observed, accompanied by a reduction in astrogliosis. Collectively, our results suggest a potential therapeutic application of DMF for patients with TDP-43-dependent FTD. Full article
(This article belongs to the Special Issue Role of NRF2 Pathway in Neurodegenerative Diseases)
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Review

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27 pages, 1525 KiB  
Review
Inflammasomes in Alzheimer’s Progression: Nrf2 as a Preventive Target
by Rubén López-Hernández, María Magdalena de la Torre-Álamo, Belén García-Bueno, Alberto Baroja-Mazo, Francisco Jose Fenoy and Santiago Cuevas
Antioxidants 2025, 14(2), 121; https://doi.org/10.3390/antiox14020121 - 21 Jan 2025
Viewed by 1380
Abstract
Current knowledge about Alzheimer’s disease highlights the accumulation of β-amyloid plaques (Aβ1–42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of [...] Read more.
Current knowledge about Alzheimer’s disease highlights the accumulation of β-amyloid plaques (Aβ1–42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of Alzheimer’s pathology. Recent advances have identified the involvement of inflammasomes, particularly NOD-like receptor NLR family pyrin domain containing 3 (NLRP3), whose activation promotes the release of proinflammatory cytokines and triggers pyroptosis, exacerbating neuroinflammation. Aggregates of Aβ1–42 and hyperphosphorylated Tau have been shown to activate these inflammasomes, while the apoptosis-associated speck-like protein (ASC) components form aggregates that further accelerate Aβ aggregation. Defects in the autophagic clearance of inflammasomes have also been implicated in Alzheimer’s disease, contributing to sustained inflammation. This review explores strategies to counteract inflammation in Alzheimer’s, emphasizing the degradation of ASC specks and the inhibition of NLRP3 inflammasome activation. Notably, the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor emerges as a promising therapeutic target due to its dual role in mitigating oxidative stress and directly inhibiting NLRP3 inflammasome formation. By reducing inflammasome-driven inflammation, Nrf2 offers significant potential for addressing the neuroinflammatory aspects of Alzheimer’s disease. Full article
(This article belongs to the Special Issue Role of NRF2 Pathway in Neurodegenerative Diseases)
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27 pages, 2646 KiB  
Review
Role of NRF2 in Pathogenesis of Alzheimer’s Disease
by Ching-Tung Chu, Akira Uruno, Fumiki Katsuoka and Masayuki Yamamoto
Antioxidants 2024, 13(12), 1529; https://doi.org/10.3390/antiox13121529 - 13 Dec 2024
Viewed by 1646
Abstract
Alzheimer’s disease (AD) is a polygenic, multifactorial neurodegenerative disorder and remains the most prevalent form of dementia, globally. Despite decades of research efforts, there is still no effective cure for this debilitating condition. AD research has increasingly focused on transcription factor NRF2 (nuclear [...] Read more.
Alzheimer’s disease (AD) is a polygenic, multifactorial neurodegenerative disorder and remains the most prevalent form of dementia, globally. Despite decades of research efforts, there is still no effective cure for this debilitating condition. AD research has increasingly focused on transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) as a potential therapeutic target. NRF2 plays a crucial role in protecting cells and tissues from environmental stressors, such as electrophiles and reactive oxygen species. Recently, an increasing number of studies have demonstrated that NRF2 is a key regulator in AD pathology. NRF2 is highly expressed in microglia, resident macrophages in the central nervous system, and contributes to neuroinflammation, phagocytosis and neurodegeneration in AD. NRF2 has been reported to modulate microglia-induced inflammation and facilitate the transition from homeostatic microglia to a disease-associated microglia subset. Genetic and pharmacological activation of NRF2 has been demonstrated to improve cognitive function. Here, we review the current understanding of the involvement of NRF2 in AD and the critical role that NRF2 plays in microglia in the context of AD. Our aim is to highlight the potential of targeting NRF2 in the microglia as a promising therapeutic strategy for mitigating the progression of AD. Full article
(This article belongs to the Special Issue Role of NRF2 Pathway in Neurodegenerative Diseases)
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21 pages, 1485 KiB  
Review
Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types
by Elisa Navarro and Noemí Esteras
Antioxidants 2024, 13(12), 1502; https://doi.org/10.3390/antiox13121502 - 10 Dec 2024
Cited by 2 | Viewed by 1595
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of cellular defence mechanisms, essential for maintaining the brain’s health. Nrf2 supports mitochondrial function and protects against oxidative damage, which is vital for meeting the brain’s substantial energy and antioxidant demands. Furthermore, [...] Read more.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of cellular defence mechanisms, essential for maintaining the brain’s health. Nrf2 supports mitochondrial function and protects against oxidative damage, which is vital for meeting the brain’s substantial energy and antioxidant demands. Furthermore, Nrf2 modulates glial inflammatory responses, playing a pivotal role in preventing neuroinflammation. This review explores these multifaceted functions of Nrf2 within the central nervous system, focusing on its activity across various brain cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Due to the brain’s vulnerability to oxidative stress and metabolic challenges, Nrf2 is emerging as a key therapeutic target to enhance resilience against oxidative stress, inflammation, mitochondrial dysfunction, and demyelination, which are central to many neurodegenerative diseases. Full article
(This article belongs to the Special Issue Role of NRF2 Pathway in Neurodegenerative Diseases)
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30 pages, 1521 KiB  
Review
The Role of NRF2 in Trinucleotide Repeat Expansion Disorders
by Kuo-Hsuan Chang and Chiung-Mei Chen
Antioxidants 2024, 13(6), 649; https://doi.org/10.3390/antiox13060649 - 26 May 2024
Cited by 4 | Viewed by 2287
Abstract
Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an [...] Read more.
Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an imbalance of reactive oxygen species that harms cellular components. This review explores the interplay between oxidative stress and the NRF2 pathway in these disorders. NRF2 acts as the master regulator of the cellular antioxidant response, orchestrating the expression of enzymes that combat oxidative stress. Trinucleotide repeat expansion disorders often exhibit impaired NRF2 signaling, resulting in inadequate responses to excessive ROS production. NRF2 activation has been shown to upregulate antioxidative gene expression, effectively alleviating oxidative stress damage. NRF2 activators, such as omaveloxolone, vatiquinone, curcumin, sulforaphane, dimethyl fumarate, and resveratrol, demonstrate neuroprotective effects by reducing oxidative stress in experimental cell and animal models of these diseases. However, translating these findings into successful clinical applications requires further research. In this article, we review the literature supporting the role of NRF2 in the pathogenesis of these diseases and the potential therapeutics of NRF2 activators. Full article
(This article belongs to the Special Issue Role of NRF2 Pathway in Neurodegenerative Diseases)
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