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Redox Active Metals in Neurodegenerative Diseases: Therapeutic Implications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 28019

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Guest Editor
Medical Faculty, Collegium Medicum, Department of Biomedical Sciences, Cardinal Stefan Wyszyński University in Warsaw, Wóycickiego Street 1/3, 01-938 Warsaw, Poland
Interests: genetics; immunology; neuroimmunology; molecular biology; autoimmune disease; neurodegeneration; stroke; metabolic disease; personalized medicine; oncology
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Special Issue Information

Dear Colleagues,

Redox-active metals play an important role in regulating various cellular pathways important for normal brain function, participating in processes such as myelination, synthesis and release of neurotransmitters, protein turnover, synthesis of neurotrophic factors, antioxidant defense and many others. The metabolism of these metals is tightly regulated by homeostatic systems, including transmembrane proteins and metallopochaperones, which regulate their absorption, intracellular localization, or excretion. Abnormalities in metal homeostasis are closely related to the onset and progression of neurodegenerative diseases. The proposal was even formulated of developing Redox Neurology as an independent subgroup of Neurology. Metal ion imbalance can induce oxidative stress, promote neuroinflammation, overproduction of amyloid-β, cause tau hyperphosphorylation, as well as mitochondrial and autophagic dysfunctions, which may initiate or intensify the aggregation of pathological forms of proteins and impair synaptic functions; it may also disrupt the function of endoplasmic organelles, causing endoplasmic stress. Changes due to metal ion imbalance can also aggravate abnormal distribution and deposition of metal ions, which can lead to chronic neurodegeneration. In recent years, the influence of redox metals on neurodegenerative diseases has been intensively studied. Despite the advances in knowledge, it is still not clear in which diseases redox active metals play a major or secondary pathogenic role, how redox active metals move from vital functions to playing a key role in pathological processes; what pathogenic mechanisms are involved in tissue damage induced by redox active metals, what protective mechanisms are disturbed in disease states. More knowledge is needed about possible therapeutic intervention strategies to prevent / reduce the pathogenic process caused or exacerbated by redox active metals.

This special issue is dedicated to the latest advances in research into the role of redox active metals in neurodegeneration. The aim is to provide an in-depth understanding of the fundamental role of copper, iron, cadmium, manganese and lesser known trace reactive metals in neurodegenerative brain diseases, and to present the results of experimental and clinical studies on pharmacological interventions to reverse metallic abnormalities that could be useful in treating common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other conditions such as stroke, multiple sclerosis, and hereditary diseases. Proposals for new therapeutic approaches to prevent and / or restore neurological changes by targeting any target at any stage of redox-active metal induced or exacerbated processes are welcome.

Prof. Dr. Grażyna Gromadzka
Guest Editor

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Published Papers (4 papers)

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Research

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14 pages, 844 KiB  
Article
Biometal Dyshomeostasis in Olfactory Mucosa of Alzheimer’s Disease Patients
by Riikka Lampinen, Veronika Górová, Simone Avesani, Jeffrey R. Liddell, Elina Penttilä, Táňa Závodná, Zdeněk Krejčík, Juha-Matti Lehtola, Toni Saari, Juho Kalapudas, Sanna Hannonen, Heikki Löppönen, Jan Topinka, Anne M. Koivisto, Anthony R. White, Rosalba Giugno and Katja M. Kanninen
Int. J. Mol. Sci. 2022, 23(8), 4123; https://doi.org/10.3390/ijms23084123 - 8 Apr 2022
Cited by 5 | Viewed by 3230
Abstract
Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer’s disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to [...] Read more.
Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer’s disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients. Full article
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17 pages, 2660 KiB  
Article
Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease
by Irina Belaya, Nina Kucháriková, Veronika Górová, Kai Kysenius, Dominic J. Hare, Peter J. Crouch, Tarja Malm, Mustafa Atalay, Anthony R. White, Jeffrey R. Liddell and Katja M. Kanninen
Int. J. Mol. Sci. 2021, 22(16), 8715; https://doi.org/10.3390/ijms22168715 - 13 Aug 2021
Cited by 14 | Viewed by 9310
Abstract
Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves [...] Read more.
Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice. Full article
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Review

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29 pages, 476 KiB  
Review
Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions
by Beata Tarnacka, Anna Jopowicz and Maria Maślińska
Int. J. Mol. Sci. 2021, 22(15), 7820; https://doi.org/10.3390/ijms22157820 - 22 Jul 2021
Cited by 52 | Viewed by 7787
Abstract
Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system [...] Read more.
Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression. Full article
31 pages, 1780 KiB  
Review
Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease
by Namdoo Kim and Hyuck Jin Lee
Int. J. Mol. Sci. 2021, 22(14), 7697; https://doi.org/10.3390/ijms22147697 - 19 Jul 2021
Cited by 32 | Viewed by 6253
Abstract
Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer’s disease (AD). Thus, regulating [...] Read more.
Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer’s disease (AD). Thus, regulating the levels of Cu(I/II) and Fe(II/III) is necessary for normal brain function. To control the amounts of metal ions in the brain and understand the involvement of Cu(I/II) and Fe(II/III) in the pathogenesis of AD, many chemical agents have been developed. In addition, since toxic aggregates of amyloid-β (Aβ) have been proposed as one of the major causes of the disease, the mechanism of clearing Aβ is also required to be investigated to reveal the etiology of AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, and ADAM10) have been reported to have an important role in the degradation of Aβ in the brain. These amyloid degrading enzymes (ADE) could interact with redox-active metal ions and affect the pathogenesis of AD. In this review, we introduce and summarize the roles, distributions, and transportations of Cu(I/II) and Fe(II/III), along with previously invented chelators, and the structures and functions of ADE in the brain, as well as their interrelationships. Full article
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