Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting 5.8 million people in the United States, including about ½ of nursing home and hospice patients. AD causes cognitive decline, resulting in extreme memory loss, often to the point where patients may not be able to recognize their own children or spouse. Most patients are in their mid-60s or older, though there is an early-onset form that affects people who are 30-60 years old. This memory loss is caused by the buildup of Amyloid-ꞵ peptides around neurons and tau in the neurons, leading to decreased activity of neurotransmitters, especially acetylcholine. At the moment, there is not much one can do to decrease the effects of Alzheimer’s disease except keep the patient safe, comfortable, and taken care of.
However, there is potential for the development of therapeutics as a result of the impact of copper and other metals in the progression of the illness. Alzheimer’s patients have modified Cu homeostasis which is important in the progression and severity of their disease. Amyloid precursor protein, which kickstarts the aggregation of Amyloid-ꞵ, has a cysteine-rich copper-binding domain in the N terminal that could possibly be targeted. AD patients also tend to have a copper deficiency within their cells as well, as the copper tends to get stuck in the protein clumps in the extracellular space.
As a result, researchers from the University of Melbourne decided to investigate the effects of copper complexes on the amalgamation of Amyloid-ꞵ. Their goal was to increase intracellular metal levels in Chinese Hamster Ovary (CHO) cells, common epithelial cells that are used in biomedical research, especially for protein therapeutics, that overexpressed the amyloid precursor protein (APP) that leads to AD. However, they did not want the copper to be released extracellularly, so they had the challenge of finding a way to keep the copper biounavailable extracellularly, but bioavailable intracellularly. In order to figure out what would be the best complex to use, they tested gts and ats copper-binding complexes to see if they would increase intracellular copper levels and reduce the formation of Amyloid-ꞵ clumps. They also tested zinc complexes as well, as zinc tends to have a similar effect as copper in AD patients. CHO cells were incubated for 6 hours, then copper and the complexes were added and incubated for 6 more hours. They then analyzed the resulting cells with Inductively Coupled Plasma Mass Spectrometry and found significant increases in intracellular copper when the cells were treated with the copper complexes compared to the copper alone or with the control. However, Aβ levels were decreased only when the copper was added in a different complex, nc or cq, which are likely more effective because the copper dissociates from the complex and becomes bioavailable more readily in the cell. The researchers also found that zinc complexes have a similar effect. Finally, they produced a theory of how this would happen in the body. They theorized that these copper complexes activate PI3K, a group of intracellular signal transducers, which results in phosphorylation of Akt, which inhibits cell death and stimulates cell proliferation, downregulation of GSK3, which regulates glycogen synthetase activity, and upregulation of JNK, a mitogen-activated protein kinase involved in tumorigenesis and neurodegeneration, overall leading to the production of metalloproteinases that break up clumps of Aβ. These results give hope that a new treatment for AD may be in sight.
Read the paper here:
Donnelly, Paul S. “Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-β Peptide,” Journal of Biological Chemistry, Volume 283, Issue 8, 2008, Pages 4568-4577, ISSN 0021-9258, https://doi.org/10.1074/jbc.M705957200