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.
Keywords: Alzheimer’s disease; Amyloid-β; Drug development; Metal chelation therapy; Metal ions; Neurodegenerative disease; Tau.
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