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Cited by 458Alzheimer's disease research and treatmentsTrace Elements in HealthDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 139 of the 140 references it cites were found in a registry or an index.

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

Open access
Wang, Lu, Yin, Ya-Ling, Liu, Xin-Zi, Shen, Peng, Zheng, Yan-Ge, Lan, Xin-Rui, Lu, Cheng-Biao, Wang, Jian-Zhi·2020·Translational Neurodegeneration
DOI 10.1186/s40035-020-00189-zPMC PMC7119290
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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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Fig. 1 Metal ions imbalance in Alzheimer-like neurodegeneration and cognitive deficits. The metal ions (Fe, Cu, Zn and Ca) imbalance induces oxidative stress demonstrated by the reduced level/activity of GSH, SOD1 and ATOX1 and an increased level of ROS. Oxidative stress can induce tau hyperphosphorylation by activating protein kinases (such as GSK-3β, CDK5, MAPK, etc.) and/or inhibiting PP2A; it can also promote Aβ overproduction by activating β- and γ-secretases and/or inhibiting α-secretase. Together with the imbalanced metal ions and oxidative stress, or independently, the hyperphosphorylated tau (p-tau) and overproduced Aβ could induce ER stress, mitochondrial dysfunction, and autophagic impairments, leading to p-tau and Aβ aggregation and accumulation. Again, together with p-tau/Aβ accumulation, autophagic/mitochondrial deficits, ER stress and oxidative stress, or independently, the imbalanced metal ions can induce synapse damages, which causes synaptic dysfunction, neurodegeneration, and eventually learning and memory deficits. As indicated in the figure by the double-sided arrows, many of these pathological processes occur in a bi-directional way and thus form a vicious cycle during the age-dependent chronic neurodegeneration, such as seen in AD
Fig. 1 Metal ions imbalance in Alzheimer-like neurodegeneration and cognitive deficits. The metal ions (Fe, Cu, Zn and Ca) imbalance induces oxidative stress demonstrated by the reduced level/activity of GSH, SOD1 and ATOX1 and an increased level of ROS. Oxidative stress can induce tau hyperphosphorylation by activating protein kinases (such as GSK-3β, CDK5, MAPK, etc.) and/or inhibiting PP2A; it can also promote Aβ overproduction by activating β- and γ-secretases and/or inhibiting α-secretase. Together with the imbalanced metal ions and oxidative stress, or independently, the hyperphosphorylated tau (p-tau) and overproduced Aβ could induce ER stress, mitochondrial dysfunction, and autophagic impairments, leading to p-tau and Aβ aggregation and accumulation. Again, together with p-tau/Aβ accumulation, autophagic/mitochondrial deficits, ER stress and oxidative stress, or independently, the imbalanced metal ions can induce synapse damages, which causes synaptic dysfunction, neurodegeneration, and eventually learning and memory deficits. As indicated in the figure by the double-sided arrows, many of these pathological processes occur in a bi-directional way and thus form a vicious cycle during the age-dependent chronic neurodegeneration, such as seen in ADCC BY · PubMed Central

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Metadata

Authors
Wang, L., Yin, Y.-L., Liu, X.-Z., Shen, P., Zheng, Y.-G., Lan, X.-R., Lu, C.-B., & Wang, J.-Z.
Affiliations
  • Henan Medical University (CN)
  • Huazhong University of Science and Technology (CN)
Corresponding author
Wang, Jian-Zhi
ORCID
Venue
Translational Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-04-03
Volume
9
Issue
1
Pages
10-10
ISSN
2047-9158 (ISSN-L)
DOI
10.1186/s40035-020-00189-z
PMC
PMC7119290
OpenAlex
W3015096020
Cited by
454
References
140
Citations by year
2026: 61 · 2025: 86 · 2024: 93 · 2023: 84 · 2022: 66 · 2021: 48 · 2020: 15
FWCI
6.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Science and Technology Department of Henan Province (182102310209)
  • National Natural Science Foundation of China (81771517, U1804197)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, metal homeostasis, iron, copper, zinc, calcium, oxidative stress, amyloid-beta, tau hyperphosphorylation, GSK3β, cyclin-dependent kinase 5, mitogen-activated protein kinase, protein phosphatase 2A, endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, synaptic dysfunction, metal chelation, metal supplementation
MeSH terms
Alzheimer Disease, Brain Chemistry, Humans, Ions, Metals, Amyloid beta-Peptides, tau Proteins

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