Current understanding of metal ions in the pathogenesis of Alzheimer’s disease
Open accessAbstract
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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In AD, metal balance is disrupted; misdistribution and pathological accumulation of these metals occur in Aβ plaques and NFTs, where they promote protein aggregation, oxidative stress, and neurotoxicity.
“However, in AD, this finely tuned balance is disrupted. Misdistribution and pathological accumulation of these metals occur in Aβ plaques and NFTs, where they promote protein aggregation, oxidative stress, and neurotoxicity [107].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [107]
The Background and Conclusions report disrupted metal-ion balance in AD and link abnormal metal distribution to Aβ/tau aggregation, oxidative stress, and neurodegeneration. The Zinc section reports elevated metal concentrations in Aβ plaques, and the Iron section links iron binding to the formation of plaques and NFTs. The copy does not establish that metals pathologically accumulate within NFTs or that all the listed effects occur specifically within plaques and NFTs. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBACE performs proteolysis by generating soluble APPβ and CTFβ; CTFβ undergoes γ-secretase proteolysis to generate toxic Aβ neuropeptides with 40-43 amino acids, finally causing the amyloid plaques characteristic of Alzheimer's disease.
“This protein known as the BACE performs proteolysis by generating a soluble fragment in the extracellular space known as “soluble APPβ” and an additional fragment bound to the plasma membrane, CTFβ peptide that undergoes proteolysis yet again by γ-secretase to generate toxic neuropeptides Aβ with 40–43 amino acids, finally causing the amyloid plaques characteristic of AD [165,166,167].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [165]
Absence of Aβ in neurons may inhibit adequate chelation of metal ions and appropriate removal of O2-, resulting in increased rather than reduced oxidative stress.
“The absence of Aβ in neurons may inhibit adequate chelation of metal ions and appropriate removal of O2-, resulting in an increased rather than a reduced oxidative stress.424”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [424]
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- 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
- Venue
- Translational Neurodegeneration
- Published
- 2020-04-03
- Volume
- 9
- Issue
- 1
- Pages
- 10-10
- ISSN
- 2047-9158 (ISSN-L)
- 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 · 2019: 1
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Health Sciences › Medicine › Physiology › 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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