The metallobiology of Alzheimer's disease
Abstract
The cause of Alzheimer's disease (AD) is closely related to the aggregation of a normal protein, beta-amyloid (Abeta), within the neocortex. Recently, evidence has been gathered to suggest that Abeta precipitation and toxicity in AD are caused by abnormal interactions with neocortical metal ions, especially Zn, Cu and Fe. However, Abeta might also participate in normal metal-ion homeostasis. An inevitable, age-dependent rise in brain Cu and Fe might hypermetallate the Abeta peptide, causing the catalysis of H(2)O(2) production that mediates the toxicity and auto-oxidation of Abeta. The greater incidence of AD in females could be due to greater constitutive activity of the synaptic Zn transporter ZnT3, and attenuated binding of metal ions to the rodent homologue of Abeta might explain why these animals are spared Alzheimer's pathology. Compounds that interdict metal-ion binding to Abeta dissolve brain deposits in vitro and one such compound, clioquinol, inhibits Abeta deposition in the Tg2576 mouse model for AD and could be useful clinically. These insights could also apply to other degenerative disorders in which metal-ion-protein interactions have been implicated.
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Metal chelators can reduce metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.
“Given the recognized interactions of Aβ with transition metal ions, several studies have shown that metal chelators can reduce the metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.43–45”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [43]
The non-specific chelator clioquinol (CQ) showed decreased Aβ aggregate formation that resulted in improved cognition in clinical trials.
“For example, the non-specific chelator clioquinol (CQ) showed decreased Aβ aggregate formation that resulted in improved cognition in clinical trials.24,25,43–45”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [43]
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- Authors
- Bush, A. I.
- Affiliations
- Mental Health Research Institute (AU)
- Corresponding author
- Bush, Ashley I.
- ORCID
- Bush, Ashley I.
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 26
- Issue
- 4
- Pages
- 207-214
- ISSN
- 0166-2236 (ISSN-L)
- OpenAlex
- W2152058429
- Cited by
- 1,315
- References
- 14
- Citations by year
- 2026: 31 · 2025: 32 · 2024: 41 · 2023: 44 · 2022: 51 · 2021: 49 · 2020: 54 · 2019: 58 · 2018: 58 · 2017: 48 · 2016: 65 · 2015: 56 · 2014: 62 · 2013: 68 · 2012: 78
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Neurosciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (2R01 AG 12686, R01AG012686)
- 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, amyloid-beta, metal ions, zinc, copper, iron, metal homeostasis, metal-protein interactions, hydrogen peroxide, autoxidation, ZnT3, sex differences, clioquinol, Tg2576 mice, metal chelators, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amebicides, Animals, Humans, Clioquinol, Metals, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Neocortex
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