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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2020

01-12-2020 | Alzheimer's Disease | Review

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Authors: Lu Wang, Ya-Ling Yin, Xin-Zi Liu, Peng Shen, Yan-Ge Zheng, Xin-Rui Lan, Cheng-Biao Lu, Jian-Zhi Wang

Published in: Translational Neurodegeneration | Issue 1/2020

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Abstract

Background

The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer’s disease (AD), the most common neurodegenerative disorder in the elderly.

Main body

Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating β- or γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogen-activated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients.

Conclusion

The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.
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Metadata
Title
Current understanding of metal ions in the pathogenesis of Alzheimer’s disease
Authors
Lu Wang
Ya-Ling Yin
Xin-Zi Liu
Peng Shen
Yan-Ge Zheng
Xin-Rui Lan
Cheng-Biao Lu
Jian-Zhi Wang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2020
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-020-00189-z

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