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Review
. 2021 Jul 19;22(14):7697.
doi: 10.3390/ijms22147697.

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer's Disease

Namdoo Kim  1 , Hyuck Jin Lee  2
Affiliations
Review

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer's Disease

Namdoo Kim et al. Int J Mol Sci. .

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.

Keywords: ADAM10; Cu(I/II); Fe(II/III); amyloid-degrading enzymes; insulin-degrading enzyme; metal chelators; neprilysin; redox-active metal ions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The roles and influence of Cu(I/II) on normal (left) and AD-affected (right) conditions.
Figure 2
Figure 2
Selected Cu(I/II)-targeting molecules developed to maintain Cu(I/II) homeostasis. Top row: 8-hydroxyquinoline (8-HQ) and its derivatives, clioquinol (CQ), 5-chloro-7-iodoquinolin-8-ol, and BPT-2, 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol; middle row: bathocuproine (BC), 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, and bathocuproine disulfonate (BCS), 4,40-(2,9-dimethyl-1,10-phenanthroline-4,7-diyl)dibenzenesulfonate; bottom row: D-penicillamine, (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid, trientine, triethylenetetramine, and tetramolybdate.
Figure 3
Figure 3
The roles and effects of Fe(II/III) in normal (left) and AD-affected (right) brains.
Figure 4
Figure 4
Representatives of Fe(II/III)-targeting molecules. Left: deferoxamine (DFO), N1-(5-aminopentyl)-N1-hydroxy-N4-(5-(N-hydroxy-4-((5-(N-hydroxyacetamido)pentyl)amino)-4-oxobutanamido)pentyl)succinamide; middle: deferiprone (DFP), 3-hydroxy-1,2-dimethylpyridin-4(1H)-one; right: bathophenanthroline disulfonate (BPS), 4,7-diphenyl-1,10-phenanthroline-3,8-disulfonate.
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