Abstract
Metal homeostasis in the central nervous system (CNS) is a crucial component of healthy brain function, because metals serve as enzymatic cofactors and are key components of intra- and inter-neuronal signaling. Metal dysregulation wreaks havoc on neural networks via induction and proliferation of pathological pathways that cause oxidative stress, synaptic impairment, and ultimately, cognitive deficits. Thus, exploration of metal biology in relation to neurodegenerative pathology is essential in pursuing novel therapies for Alzheimer’s Disease and other neurodegenerative disorders. This review covers mechanisms of action of aluminum, iron, copper, and zinc ions with respect to the progressive, toxic accumulation of extracellular β-amyloid plaques and intracellular hyperphosphorylated neurofibrillary tau tangles that characterizes Alzheimer’s Disease, with the goal of evaluating the therapeutic potential of metal ion interference in neurodegenerative disease prevention and treatment. As neuroscientific interest in the role of metals in neurodegeneration escalates—in large part due to emerging evidence substantiating the interplay between metal imbalances and neuropathology—it becomes clear that the use of metal chelating agents may be a viable method for ameliorating Alzheimer’s Disease pathology, as its etiology remains obscure. We conclude that, although metal therapies can potentially deter neurodegenerative processes, the most promising treatments will remain elusive until further understanding of neurodegenerative etiology is achieved. New research directions may best be guided by animal models of neurodegeneration, which reveal specific insights into biological mechanisms underlying dementia.
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Acknowledgements
This study was supported by funding from the National Center for Toxicological Research/FDA [Protocol #763101 to SS]
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This study was supported by funding from the National Center for Toxicological Research/FDA [Protocol #763101 to SS].
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Nikita Das (ND) is the lead author who has substantially contributed in writing the manuscript. James Raymick (JR) has significant input on histological labeling of sections, data collection. Sumit Sarkar (SS) is the corresponding author and primary input on experiment design, performed animal sacrifice, tissue processing and immune-labeling of histological sections, data collection and interpretation of photomicrographs and editing of manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All experimental procedures described here for rodent and human tissues were approved by the appropriate committees at the National Center for Toxicological Research/FDA, including the NCTR Office of Research, the Regulatory Compliance and Risk Management Director and the FDA Research Involving Human Subjects Committee (RIHSC). As determined by the FDA RIHSC, this study did not reach the definition of “Human Subject Research” at 45 CFR 46.102(f) and thus, 45 CFR Part 46 does not apply.
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Das, N., Raymick, J. & Sarkar, S. Role of metals in Alzheimer’s disease. Metab Brain Dis 36, 1627–1639 (2021). https://doi.org/10.1007/s11011-021-00765-w
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DOI: https://doi.org/10.1007/s11011-021-00765-w