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 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.
Highlights
In the human brain, various metal ions are essential as cofactors for numerous enzymes for catalytic activities and neurotransmission including synaptic plasticity, myelination, and synthesis of neurotransmitters [1,2]
Defects in energy metabolism, aberrant axonal transport, and inflammation have been observed which potentially lead to neurodegenerative disorders [7,8,9,10]
In order to reduce the risk of neurodegeneration by Cu(I/II) and/or Fe(II/III), the metal chelation strategy has been suggested as the treatment of Alzheimer’s disease (AD); only targeting metal ions could not cure the disease completely
Summary
Various metal ions are essential as cofactors for numerous enzymes for catalytic activities and neurotransmission including synaptic plasticity, myelination, and synthesis of neurotransmitters [1,2]. The redox-active metal ions, Cu(I/II) and Fe(II/III), could be related to neuronal impairments, subsequently leading to cognitive defects. In addition to redox-active metal ions, clearance of Aβ in the brain is critical for ameliorating neurotoxicity. We summarize the distributions and roles of redox-active metal ions [i.e., Cu(I/II) and Fe(II/III)] in both healthy and diseased brains, as well as previously developed chemicals to regulate the levels of those metal ions. It works as a cofactor that binds to various metalloenzymes and assists their activation [4,21] Since it usually exists as cuprous ions [Cu(I)] and cupric ions [Cu(II)], Cu(I/II) can serve as an electron transporter. Several regions of the brain such as the soma of cortical pyramidal and cerebellar granular neurons, the hippocampus, the cerebellum, and the spinal cord have labile copper stores [27]. There are labile pools with a low concentration in the extracellular regions [34]
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