Alzheimer’s Disease Background
Alzheimer’s Disease (AD) is classified as a neurocognitive disorder, often displayed by decline in cognitive function, such as dementia, and motor control. Most cases of AD surface around the age of 65, and currently, approximately 44 million cases of it exist worldwide.
There are two primary markers of AD pathology. First, are the neurofibrillary tangles (NFTs), which are caused by aggregates of hyperphosphorylated tau protein that create insoluble twisted fibers in neuronal cells. The second marker is amyloid plaque buildup. Amyloid plaque is caused by aggregates of A-beta peptide in the synapses of neurons. The plaque’s role in cognitive decline is that it blocks the transmission of neurotransmitters, and it is toxic to cells. A-beta peptide is created by the amyloid protein precursor (APP) gene in the 21st chromosome (which is why AD is so prevalent in adult patients with Down’s Syndrome).
Nanoparticles as treatment
Recent in vitro research on amyloid plaque induced cell cultures has yielded potential criterion for AD nanoparticle treatment. When performing the experiment, the experimenters1 used CdTe nanoparticles for their tetrahedral shape to disrupt the A-beta protein aggregates. They found the sharper “edges” of the tetrahedral nanoparticles to be successful in this purpose, however, CdTe is not biocompatible, and thus would not be successful in vivo. In accordance with the past research, our project intends to factor in the shape of nanoparticles, while searching for a biocompatible alternative.
C60 Fullerene and Its Derivatives
C60 is a nanoparticle created in the 1990s and currently has potential applications to a number of medical conditions that are being explored. It can be used to research treatments of cancer, viral infections, neurodegenerative diseases, and drug tolerances because of its antioxidant, antibacterial, and antiproliferative properties.
C60’s structure is of a spherical shape made of pentagons and hexagons with slightly sharper edges that could potentially meet the criteria needed to disrupt A-beta protein aggregates.
The other benefit of using C60 itself is that it can accept a large number of radical electrons to stabilize the unstable ROS.
Cystine-functionalized C60: The amino acid Cystine, once taken up by cells, is broken down into Cysteine. This is an essential amino acid to the human body that produces glutathione, an antioxidant that reduces oxidative stress (for more information on oxidative stress and reactive oxygen species refer to the Parkinson’s page) in cells and protects cells from other toxins. Since one of the methods of amyloid plaque’s is oxidative stress2 , cystine functionalization would be beneficial. The other benefits of cystine are that it is water soluble, which would help the fullerene pass the phospholipid bilayer of the cell membrane, and that cysteine increases the production of taurine in neural cells. Taurine is an amino acid that is in low concentration in AD patients. Taurine can inhibit the aggregation of amyloid-β-peptide and can promote tau protein polymerization.3
Selenium-functionalized C60: Selenium (Se) is a antioxidant bioactive compound that, based on current literature, has potential to be a strong therapeutic for AD. Research on the etiology of AD by NIH further explored the roles of Reactive Oxygen Species (ROS) and oxidative stress in the pathogenesis of AD. The research found that Se levels were low in the blood of AD patients and that Se disrupted Aβ formation through decreasing ROS production4.
Experimentation
In an ideal experiment testing the effect of C60 and its derivatives on treating amyloid plaque symptom of AD, there would be 5 test groups with 4 or more trials:
Test Group 1 (Neutral Control): neuronal cell culture to provide baseline of neural firing rates
Test Group 2 (Negative Control): neuronal cell culture with A-beta peptide aggregate to provide baseline model of firing rates in patients
Test Group 3: neuronal cell culture + A-beta peptide + C60
Test Group 4: neuronal cell culture + A-beta peptide + Cystine-functionalized C60
Test Group 5: neuronal cell culture + A-beta peptide + Selenium-functionalized C60
After cultures are created and nanoparticles are administered, the cultures would be looked at and monitored under the microscope at 100x to ensure that nanoparticles have entered the cell.
Testing
Since AD – as a neurodegenerative disease – causes decrease in neural transmissions and failure of neural pathways, a proper measurement of C60 (and derivatives) effectiveness would be to measure electrical activity. To do this, the project would make use of microelectrode arrays (MEAs) that are hooked up to Matlab to measure the Sodium and Potassium channels as well as the electrical activity.
Bibliography:
1 Yoo, S. I., Yang, M., Brender, J. R., Subramanian, V., Sun, K., Joo, N. E., . . . Kotov, N. A. (2011, May 11). Inside Cover: Inhibition of Amyloid Peptide Fibrillation by Inorganic Nanoparticles: Functional Similarities with Proteins (Angew. Chem. Int. Ed. 22/2011) – Yoo – 2011 – Angewandte Chemie International Edition – Wiley Online Library. Retrieved from https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201102689
2 Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., & Collin, F. (2018, April). Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29080524
3 Santa-María, I., Hernández, N., Moreno, J., & Avila, J. H. (1970, January 01). Taurine, an inducer for tau polymerization and a weak inhibitor for amyloid-β-peptide aggregation – Semantic Scholar. Retrieved from https://www.semanticscholar.org/paper/Taurine,-an-inducer-for-tau-polymerization-and-a-Santa-María-Hernández/b2429de187831c7c134e4beaeabf3c5ec236aa38
4 Nazıroğlu, M., Muhamad, S., & Pecze, L. (2017, July). Nanoparticles as potential clinical therapeutic agents in Alzheimer’s disease: Focus on selenium nanoparticles. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28463572