Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)
Abstract
This review covers copper homeostasis and its eventual link with copper involvement in different neurological disorders. Copper plays a dual role in producing reactive oxygen species: damaging the cells and eliciting antioxidant activity. Abnormal binding of metal ions to proteins or losing control over the copper homeostasis can result in disorders including neurodegenerative diseases. In addition to creating oxidative stress, copper, together with other metal ions influences protein aggregation processes that are critical in most of the neurodegenerative diseases.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These metal ions have been shown to promote Aβ40 aggregation.
“Thus, these metal ions have been shown to promote Aβ40 aggregation,23–27,29–32”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [29]
These metal ions lead to formation of reactive oxygen species (ROS) and oxidative stress.
“as well as lead to formation of reactive oxygen species (ROS) and oxidative stress.3,26–31,33–36”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [29]
Use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ-metal species exhibit adverse side effects that will likely limit their long term clinical use.
“However, use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ–metal species exhibit adverse side effects that will likely limit their long term clinical use.3,28,29,31,44,46–48”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [29]
The pM values compare favorably with Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).
“These pM values represent approximate dissociation constants and compare favorably with the Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).26,29,31,57,76,79,80”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [29]
This is in contrast with a large number of reports showing the aggregation-promoting effect of metal ions on the Aβ peptide.
“This is in contrast with a large number of reports showing the aggregation-promoting effect of metal ions on the Aβ peptide.23–27,29–32,37,38”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [29]
Cites
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · see citing works
Neurodegenerative diseases and oxidative stress
Barnham, K. J., Masters, C. L., & Bush, A. I. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1330 · Cited by 3,683 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599 · see citing works
Candidate gene for the chromosome 1 familial Alzheimer’s disease locus
Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C.-E., Jondro, P. D., Schmidt, S. D., Wang, K., et al. (1995) · Science · doi:10.1126/science.7638622 · Cited by 2,577 · see citing works
Cobbett, C., & Goldsbrough, P. (2002) · Annual Review of Plant Biology · doi:10.1146/annurev.arplant.53.100301.135154 · Cited by 2,518 · see citing works
Copper, iron and zinc in Alzheimer's disease senile plaques
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., & Markesbery, W. R. (1998) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(98)00092-6 · Cited by 2,120 · see citing works
Amyloid β Protein Gene: cDNA, mRNA Distribution, and Genetic Linkage Near the Alzheimer Locus
Tanzi, R. E., Gusella, J. F., Watkins, P. C., Bruns, G. A. P., St George-Hyslop, P., Van Keuren, M. L., Patterson, D., Pagan, S., Kurnit, D. M., & Neve, R. L. (1987) · Science · doi:10.1126/science.2949367 · Cited by 1,611 · see citing works
Rapid induction of Alzheimer A beta amyloid formation by zinc
Bush, A., Pettingell, W., Multhaup, G., d Paradis, M., Vonsattel, J., Gusella, J., Beyreuther, K., Masters, C., & Tanzi, R. (1994) · Science · doi:10.1126/science.8073293 · Cited by 1,522 · see citing works
Unfolding the role of protein misfolding in neurodegenerative diseases
Soto, C. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1007 · Cited by 1,506 · see citing works
Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y.-S., et al. (2001) · Neuron · doi:10.1016/s0896-6273(01)00317-8 · Cited by 1,447 · see citing works
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., et al. (2001) · Nature · doi:10.1038/35102591 · Cited by 1,388 · see citing works
Giasson, B. I., Murray, I. V. J., Trojanowski, J. Q., & Lee, V. M.-Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008919200 · Cited by 1,080 · see citing works
Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M. E., Romano, D. M., Hartshorn, M. A., Tanzi, R. E., & Bush, A. I. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.21.12817 · Cited by 1,009 · see citing works
Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity
Huang, X., Cuajungco, M. P., Atwood, C. S., Hartshorn, M. A., Tyndall, J. D. A., Hanson, G. R., Stokes, K. C., Leopold, M., Multhaup, G., Goldstein, L. E., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37111 · Cited by 762 · see citing works
Bush, A. (2000) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(99)00073-3 · Cited by 731 · see citing works
Aqueous Dissolution of Alzheimer's Disease Aβ Amyloid Deposits by Biometal Depletion
Cherny, R. A., Legg, J. T., McLean, C. A., Fairlie, D. P., Huang, X., Atwood, C. S., Beyreuther, K., Tanzi, R. E., Masters, C. L., & Bush, A. I. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.33.23223 · Cited by 482 · see citing works
Gabuzda, D., Busciglio, J., Chen, L. B., Matsudaira, P., & Yankner, B. A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36875-8 · Cited by 373 · see citing works
Misonou, H., Morishima-Kawashima, M., & Ihara, Y. (2000) · Biochemistry · doi:10.1021/bi000169p · Cited by 304 · see citing works
New Insights on How Metals Disrupt Amyloid β-Aggregation and Their Effects on Amyloid-β Cytotoxicity
Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N., & Takashima, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010706200 · Cited by 244 · see citing works
Amyloid-β is an antioxidant for lipoproteins in cerebrospinal fluid and plasma
Kontush, A., Berndt, C., Weber, W., Akopyan, V., Arlt, S., Schippling, S., & Beisiegel, U. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00458-5 · Cited by 180 · see citing works
Kowalik-Jankowska, T., Ruta, M., Wiśniewska, K., Łankiewicz, L., & Dyba, M. (2004) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.03.001 · Cited by 92 · see citing works
Daniele, P. G., Zerbinati, O., Zelano, V., & Ostacoli, G. (1991) · J. Chem. Soc., Dalton Trans. · doi:10.1039/dt9910002711 · Cited by 49 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Small-Molecule Two-Photon Probes for Bioimaging Applications
Kim, H. M., & Cho, B. R. (2015) · Chemical Reviews · doi:10.1021/cr5004425 · Cited by 1,047 · see citing works
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554 · see citing works
Using Graphene Oxide High Near‐Infrared Absorbance for Photothermal Treatment of Alzheimer's Disease
Li, M., Yang, X., Ren, J., Qu, K., & Qu, X. (2012) · Advanced Materials · doi:10.1002/adma.201104864 · Cited by 535 · see citing works
Zheng, W., & Monnot, A. D. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.10.006 · Cited by 302 · see citing works
Choi, J.-S., Braymer, J. J., Nanga, R. P. R., Ramamoorthy, A., & Lim, M. H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006091107 · Cited by 264 · see citing works
Hureau, C., & Faller, P. (2009) · Biochimie · doi:10.1016/j.biochi.2009.03.013 · Cited by 259 · see citing works
Metal based neurodegenerative diseases—From molecular mechanisms to therapeutic strategies
Crichton, R. R., Dexter, D. T., & Ward, R. J. (2008) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2007.10.019 · Cited by 252 · see citing works
Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus
Ashraf, G., Greig, N., Khan, T., Hassan, I., Tabrez, S., Shakil, S., Sheikh, I., Zaidi, S., Akram, M., Jabir, N., et al. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666140917095514 · Cited by 236 · see citing works
Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide
Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J., & Mirica, L. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja210588m · Cited by 202 · see citing works
Minding metals: Tailoring multifunctional chelating agents for neurodegenerative disease
Perez, L. R., & Franz, K. J. (2010) · Dalton Trans. · doi:10.1039/b919237a · Cited by 156 · see citing works
Storr, T., Merkel, M., Song-Zhao, G. X., Scott, L. E., Green, D. E., Bowen, M. L., Thompson, K. H., Patrick, B. O., Schugar, H. J., & Orvig, C. (2007) · Journal of the American Chemical Society · doi:10.1021/ja068965r · Cited by 156 · see citing works
Iodine-Stabilized Cu Nanoparticle Chitosan Composite for Antibacterial Applications
Mallick, S., Sharma, S., Banerjee, M., Ghosh, S. S., Chattopadhyay, A., & Paul, A. (2012) · ACS Applied Materials & Interfaces · doi:10.1021/am201586w · Cited by 152 · see citing works
Why is the amyloid beta peptide of Alzheimer’s disease neurotoxic?
Rauk, A. (2008) · Dalton Transactions · doi:10.1039/b718601k · Cited by 139 · see citing works
Li, M., Guan, Y., Zhao, A., Ren, J., & Qu, X. (2017) · Theranostics · doi:10.7150/thno.18459 · Cited by 90 · see citing works
Scott, L. E., Telpoukhovskaia, M., Rodríguez-Rodríguez, C., Merkel, M., Bowen, M. L., Page, B. D. G., Green, D. E., Storr, T., Thomas, F., Allen, D. D., et al. (2011) · Chem. Sci. · doi:10.1039/c0sc00544d · Cited by 68 · see citing works
Braymer, J. J., DeToma, A. S., Choi, J.-S., Ko, K. S., & Lim, M. H. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/623051 · Cited by 50 · see citing works
Synthesis and characterization of IMPY derivatives that regulate metal-induced amyloid-β aggregation
Choi, J.-S., Braymer, J. J., Park, S. K., Mustafa, S., Chae, J., & Lim, M. H. (2011) · Metallomics · doi:10.1039/c0mt00077a · Cited by 41 · see citing works
Reactivity of Diphenylpropynone Derivatives Toward Metal-Associated Amyloid-β Species
Pithadia, A. S., Kochi, A., Soper, M. T., Beck, M. W., Liu, Y., Lee, S., DeToma, A. S., Ruotolo, B. T., & Lim, M. H. (2012) · Inorganic Chemistry · doi:10.1021/ic302084g · Cited by 38 · see citing works
Liquid-liquid phase separation in Alzheimer’s disease
Fu, Q., Zhang, B., Chen, X., & Chu, L. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02407-3 · Cited by 33 · see citing works
Rai, R. K., Chalana, A., Karri, R., Das, R., Kumar, B., & Roy, G. (2019) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.8b03212 · Cited by 19 · see citing works
Tabbì, G., Magrì, A., Giuffrida, A., Lanza, V., Pappalardo, G., Naletova, I., Nicoletti, V. G., Attanasio, F., & Rizzarelli, E. (2015) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2014.09.008 · Cited by 18 · see citing works
Magrì, A., Tabbì, G., Giuffrida, A., Pappalardo, G., Satriano, C., Naletova, I., Nicoletti, V. G., & Attanasio, F. (2016) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2016.08.013 · Cited by 9 · see citing works
Tomasello, M. F., Di Rosa, M. C., Naletova, I., Sciacca, M. F. M., Giuffrida, A., Maccarrone, G., & Attanasio, F. (2025) · Bioinorganic Chemistry and Applications · doi:10.1155/bca/4226220 · Cited by 3 · see citing works
- Authors
- Gaggelli, E., Kozlowski, H., Valensin, D., & Valensin, G.
- Affiliations
- University of Siena (IT)
- Department of Chemistry, University of Siena, Via Aldo Moro 2, Siena 53100, Italy, and Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
- ORCID
- Valensin, Daniela
- Venue
- Chemical Reviews
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-06-01
- Volume
- 106
- Issue
- 6
- Pages
- 1995-2044
- ISSN
- 0009-2665 (ISSN-L)
- 1520-6890
- OpenAlex
- W1991039509
- Cited by
- 1,729
- References
- 24
- Citations by year
- 2026: 44 · 2025: 80 · 2024: 104 · 2023: 90 · 2022: 100 · 2021: 77 · 2020: 102 · 2019: 116 · 2018: 96 · 2017: 112 · 2016: 103 · 2015: 109 · 2014: 110 · 2013: 102 · 2012: 105
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Reviews (publishedVersion)
- PubMed (publishedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Keywords
- copper homeostasis, neurodegenerative diseases, Alzheimer's disease, prion disease, Parkinson's disease, amyotrophic lateral sclerosis, reactive oxygen species, oxidative stress, metalloprotein binding, protein aggregation, metal ions
- MeSH terms
- Adenosine Triphosphatases, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Animals, Copper, Histidine, Homeostasis, Humans, Models, Chemical, Models, Molecular, Molecular Conformation, Parkinson Disease, Protein Binding, Molecular Structure, Amyloid beta-Peptides, Prion Diseases, Oxidative Stress, Neurodegenerative Diseases, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
