The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy

Rao, Shalini S; Portbury, Stuart; Lago, Larissa; Bush, Ashley I.; Adlard, Paul A.

doi:10.3233/jad-209009

Cited by 20 publications

(14 citation statements)

References 82 publications

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“…Inspiringly, several studies have shown favorable therapeutic effects of ferroptosis inhibitors on AD animals ( Zhang et al, 2018 ; Komaki et al, 2019 ; Rao et al, 2020 ; Farr and Xiong, 2021 ). The iron chelators DFO and DFP are widely used as specific inhibitors of ferroptosis.…”

Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

“…The iron chelators DFO and DFP are widely used as specific inhibitors of ferroptosis. Preclinical evidence suggests that iron chelators modulate iron homeostasis, mitigate oxidative distress, improve cognition and behavioral outcomes in AD mice ( Rao et al, 2020 ; Farr and Xiong, 2021 ). CoQ10 has been shown to inhibit ferroptosis in AD mice by inhibiting lipid peroxidation.…”

Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

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Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.

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Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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“…twice daily/5 days/week for 24 months) resulted in a significant reduction in the rate of decline of daily living skills in 48 AD patients, compared to AD patients receiving a placebo [113]. Another iron chelator, deferiprone has shown promising results in a mouse model [114]. However, only few metal chelating agents have been examined in clinical trials for the treatment of AD in recent years, viz.…”

Section: Metal Chelation-a Rational Strategy?mentioning

confidence: 99%

Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease

Aaseth

Skalny

Roos

et al. 2021

IJMS

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The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer’s disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.

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“…Unlike the pore‐forming molecules in pyroptosis or necroptosis, the executioner of ferroptosis is overwhelming ROS‐driven lipid peroxidation causing cell failure and membrane rupture. There have been some reports implicating iron accumulation and ferroptosis in neurologic disease and ALS 117,193,203 . For example, Wang et al found that transgenic overexpression of GPX4 increased motor performance and survival in the SOD1 G93A mouse model 193,194 .…”

Section: Ferroptosis In Alsmentioning

confidence: 99%

“…There is considerable evidence suggesting that caspase activity promotes cell death and inflammation in mouse models of ALS and neurodegeneration 14,54,79,151,203,204,205 . That caspase‐1 and caspase‐3 regulate distinct cell death pathways (pyroptosis and apoptosis, respectively), suggesting that a pan‐caspase inhibition strategy may have clinical benefit.…”

Section: New Leads: Potential Therapeutic Strategies Targeting Progra...mentioning

confidence: 99%

Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis

Neel

Basu

Gunner

et al. 2022

Immunological Reviews

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For the organism to live, some cells must die. Seminal studies in developmental biology have shown that normal development and tissue homeostasis rely upon programmed cell death (PCD). For instance, the death of cells in the apical ectodermal ridge sculpts the digits of developing vertebrate limbs during embryogenesis. 1,2 Early work mapped morphological features of cells in the process of "orderly" elimination. 3 Collectively, these features-cytoplasmic shrinkage, nuclear condensation, fragmentation, and the budding small bodies-were termed "apoptosis." 3 The central nervous system (CNS), comprised of the brain and spinal cord, is sculpted by apoptotic events in neural precursor cells (NPCs), differentiated post-mitotic neurons, and glial cells. 4 Only the cells with appropriate connections, location, size, and shape are needed for CNS homeostasis. Superfluous neurons are eliminated, and axonal projections "pruned". Between birth and adulthood, humans lose an estimated 15% of their neurons. 5 In transgenic mice lacking effectors of apoptosis (such as Apaf-1 and caspase-3/9), the CNS is the most affected tissue, presenting with a glut of neurons contained in disorganized structures. 6,7 Collectively, studies describing the process of neurodevelopment highlight the importance of apoptotic cell death in sculpting normal CNS architecture. 4,8 Although life begins with elimination of unwanted neurons and is necessary for proper development, aberrant death of distinct CNS regions is a hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and

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The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy

Cited by 20 publications

References 82 publications

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease

Catching a killer: Mechanisms of programmed cell death and immune activation in Amyotrophic Lateral Sclerosis

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