Copper is a crucial metal in the body, involved in the production of red blood cells, supporting the immune response, and aiding in cellular energy production. The main dietary sources of copper include foods such as beans, shellfish, and potatoes. Copper is absorbed in the intestines, and excess copper is excreted by the liver. While copper is an essential metal, excessive levels can have dire implications. This is because copper contributes to the formation of reactive oxygen species (ROS). ROS are highly reactive molecules containing oxygen that can damage DNA and proteins within cells. As we age, ROS accumulation increases due to enzyme dysregulation and the reduced efficiency of protein function over time.
Neurodegenerative disorders (ND) are diseases associated with the destruction of neurons in the brain. This results in the disruption of processes mediated by the brain, such as movement, behavior, and cognition. The most common symptom of ND is memory loss (dementia). Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the leading causes of dementia. The processes at the onset and the exact causes of these diseases remain unknown since they are primarily diagnosed in the symptomatic stages when significant brain damage has already occurred. Because of copper’s capacity to form ROS and damage proteins and neurons, excess copper in brain cells has been implicated in the development of typical markers of ND. Consequently, the role of copper in ND has been a significant area of research.
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta plaques in the brain. Amyloid beta is a protein that facilitates the transmission of impulses, aiding in learning and memory retention. The levels of amyloid beta are maintained by microglia (the immune cells of the brain), which engulf and destroy excess protein through a process called phagocytosis. Microglia are activated by signals such as neuronal damage, initiating immune responses known as inflammation. Inflammation is mediated by proteins called cytokines, which stimulate specific immune responses. When this process is disrupted, amyloid beta accumulates into plaques, which have been observed in brain scans of AD patients. These features contribute to dementia, as disruptions in amyloid beta pathways interfere with memory creation and retention processes in the hippocampus.
Researchers from UC Irvine hypothesized that copper exposure perturbs the regulation of amyloid beta plaques, potentially contributing to their accumulation in the brain.The brain’s pathways for clearing amyloid beta (Aβ) from the parenchyma can be disrupted, resulting in its accumulation. Using murine (mouse) microglial cells as a model, researchers performed phagocytosis assays on cells injected with synthetic Aβ under physiological conditions and in a medium containing 0.5 µM copper. They found that cells exposed to copper exhibited reduced inflammatory activation and lower expression of the YM-1 phagocytosis marker. Additionally, microglial cells exposed to Aβ under elevated copper conditions secreted increased levels of pro-inflammatory cytokines, which hinder Aβ clearance and, in excess, cause neuronal damage.
In vivo studies on human microvascular endothelial cells revealed that copper exposure downregulates LRP1 (low-density lipoprotein receptor-related protein 1), a protein responsible for clearing Aβ across the blood-brain barrier and directing it to degradation. Furthermore, exposing the 3xTg-AD mouse model of Alzheimer’s disease to copper in drinking water resulted in significant activation of microglia as early as three months. However, staining of the microglia showed a significantly reduced number of phagocytically active cells in the Alzheimer’s model compared to the control group. Copper-exposed 3xTg-AD mice(mice model of AD) also exhibited downregulated LRP1 protein expression and increased secretion of pro-inflammatory cytokines. This study highlighted copper’s role in disrupting amyloid beta clearance by impairing the microglial inflammatory response.
Parkinson’s disease (PD), another cause of dementia, arises from the loss of dopaminergic neurons, which affects voluntary movement and memory. These neurons produce dopamine, a compound that facilitates the transmission of nerve impulses between neurons. Similar to Alzheimer’s, PD is also characterized by protein aggregates; in this case, alpha-synuclein, a protein that regulates dopamine release, is implicated. Misfolded forms of alpha-synuclein have been found in Lewy bodies present in the brains of PD patients, indicating their involvement in the disease. Alpha-synuclein also mediates pathways maintaining energy balance in dopaminergic neurons, and disruption of its structure results in metabolic dysregulation and neuronal death observed in PD.
a,Two pigmented nerve cells, each containing an α-synuclein-positive Lewy body (thin arrows). Lewy neurites (thick arrows) are also immunopositive. Scale bar, 20 μm. b, A pigmented nerve cell with two α-synuclein-positive Lewy bodies. Scale bar, 8 μm. c, α-Synuclein-positive, extracellular Lewy body. Scale bar, 4 μm.
A second study investigated how copper in the brain modulates the phosphorylation of alpha-synuclein. Phosphorylation is a process where a phosphate group is added to a protein’s structure by enzymes called kinases, altering the protein’s function. While phosphorylation is often regulatory, excessive phosphorylation increases alpha-synuclein’s susceptibility to misfolding and aggregation.To model dopaminergic neurons, researchers used SH-SY5Y neuroblastoma cells, immature nerve cells that can differentiate into neurons. Retinoic acid was used to induce differentiation, promoting the expression of genes necessary for mature neuronal function. Differentiation was confirmed by detecting specific differentiation markers. Some differentiated cells were then exposed to copper for 48 hours, and the levels of phosphorylated (p-α-Syn) and unphosphorylated (Syn) alpha-synuclein were measured. The researchers found significantly elevated levels of phosphorylated alpha-synuclein in the copper-exposed differentiated cells compared to the control group.
To confirm these results, they measured the expression of PLK2 kinase, an enzyme that phosphorylates alpha-synuclein at the Serine 129 amino acid. Copper exposure increased PLK2 kinase expression in the differentiated cells compared to controls. Interestingly, the expression of PP2AC phosphatase, an inhibitor of PLK2 kinase, was not affected by copper exposure. These findings demonstrated that differentiated dopaminergic-like cells exposed to copper for 48 hours experienced elevated levels of phosphorylated alpha-synuclein, a phenomenon linked to PD, likely due to increased PLK2 kinase activity.
In summary, copper accumulation in the brain is implicated in the pathological processes of both Alzheimer’s and Parkinson’s diseases. This underscores the need for further research, as understanding the interactions between copper and key proteins—amyloid beta and alpha-synuclein—could enhance knowledge of the mechanisms underlying these neurodegenerative disorders.
Sources:
An, Y., Li, S., Huang, X., Chen, X., Shan, H., & Zhang, M. (2022). The Role of Copper Homeostasis in Brain Disease. International journal of molecular sciences, 23(22), 13850. https://doi.org/10.3390/ijms232213850
Greco, M., Spinelli, C. C., De Riccardis, L., Buccolieri, A., Di Giulio, S., Musarò, D., Pagano, C., Manno, D., & Maffia, M. (2021). Copper Dependent Modulation of α-Synuclein Phosphorylation in Differentiated SHSY5Y Neuroblastoma Cells. International journal of molecular sciences, 22(4), 2038. https://doi.org/10.3390/ijms22042038
Kitazawa, M., Hsu, H. W., & Medeiros, R. (2016). Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta. Toxicological sciences : an official journal of the Society of Toxicology, 152(1), 194–204. https://doi.org/10.1093/toxsci/kfw081