The brain is the most complex organ in the human body. As one ages, the structure, function, and connectivity of the brain changes. Alzheimer’s disease is a degenerative brain disease, namely characterized by memory loss, and is a clear example of these changes in the brain (Alzheimer’s Association, 2015). This disease is the most common type of dementia (Wilson et al., 2012), and it is estimated that 5.3 million people have Alzheimer’s disease in the United States alone (Alzheimer’s Association, 2015). The cause of the disease is the failure of synapses in the brain as a result of the accumulation of the proteins beta-amyloid outside neurons and tau inside neurons (Alzheimer’s Association, 2015). However, the exact biological processes that cause this disease are unknown. There are two popular theories that attempt to make sense of the biological processes of Alzheimer’s disease; the process of myelination and iron content in the brain.
One theory that attempts to explain the biological process that causes Alzheimer’s disease is focused on myelination in the brain. In order for the brain to function, neurons transmit signals to one another through action potentials. In the vertebrate brain, the speed and efficiency of these action potentials depend on myelin (Emery, 2010). Myelin is a structure generated by glial cells that is wrapped around axons of neurons (Figure 1). It consists of proteins and phospholipids, and is formed by oligodendrocytes (Emery, 2010).
Some researchers believe myelin is the “weakest link” in the brain, and that improper maintenance and repair of myelin can cause various neurodegenerative diseases, Alzheimer’s disease included (Bartzokis, 2011). In mice that exhibit symptoms of Alzheimer’s disease, it has been shown that myelination is disrupted even during the earliest stages of Alzheimer’s disease in sub regions of the entorhinal cortex (Desai et al., 2009). Granulation in myelin sheaths in the hippocampus has been observed in mice with Alzheimer’s, and it is clear that the number of dystrophic axons is related to the percent of granulated axonal myelin, as seen in Figure 2 (Desai et al., 2009). This shows that decline in myelination does cause deterioration of neuronal pathways in the brain, which is thought to lead to Alzheimer’s disease.
Another theory thought to explain the biological process that causes Alzheimer’s revolves around levels of iron in the brain. It is known that during Alzheimer’s disease, Zn2+ collects with beta-amyloid in extracellular plaques, mostly in the amygdala, hippocampus, and inferior parietal lobe, (Deibel, Ehmann and Markesbery, 1996) adjacent to neurons filled with pro-oxidant Fe2+ (Duce et al., 2010). Beta-amyloid is derived from a transmembrane protein precursor called APP, which possesses ferroxidase activity. Ferroxidases prevent oxidative stress, as they normally oxidize Fe2+ to Fe3+ (Duce et al., 2010). APP ferroxidase activity is inhibited by the Zn2+ in the extracellular plaques, which has the result of increased amounts of iron in the brain due to the fact that there is less APP to oxidize Fe2+ to Fe3+ (Duce et al., 2010). Increased levels of iron in the brain affect the parenchyma and the dystrophic neurites of amyloid plaques, which is thought to be a mechanism that causes Alzheimer’s disease. Levels of Zn2+ and iron in the brain may indicate the onset of Alzheimer’s.
Alzheimer’s disease affects a great number of people, and it is important to understand its causation in order to begin to develop effective methods to screen for and treat the disease. Further research must be done into the connection between myelination and iron and the onset of the disease, as these biomarkers may prove to be a useful method to screen for Alzheimer’s. As the world’s population rapidly ages, it is essential to invest resources in this as of now incurable disease.
References:
Alzheimer’s Association, 2015. 2015 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 11(3), p.332-384.
Bartzokis, G., 2011. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiology of Aging, 32(8), p.1341-1371.
Deibel, M., Ehmann, W. and Markesbery, W., 1996. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. Journal of the Neurological Sciences, 143(1-2), p.137-142.
Desai, M., Sudol, K., Janelsins, M., Mastrangelo, M., Frazer, M. and Bowers, W., 2009. Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia, 57(1), p.54-65.
Duce, J., Tsatsanis, A., Cater, M., James, S., Robb, E., Wikhe, K., Leong, S., Perez, K., Johanssen, T., Greenough, M., Cho, H., Galatis, D., Moir, R., Masters, C., McLean, C., Tanzi, R., Cappai, R., Barnham, K., Ciccotosto, G., Rogers, J. and Bush, A., 2010. Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer’s Disease. Cell, 142(6), p.857-867.
Emery, B., 2010. Regulation of Oligodendrocyte Differentiation and Myelination. Science, 330(6005), p.779-782.
University of Colorado Springs, n.d.. Myelin sheath. [image online]. Available at:<http://www.uccs.edu/biology-educational-resources/mood-disorders/bipolar-disorder.html> [Accessed 22 Feb 2017].
Wilson, R., Segawa, E., Boyle, P., Anagnos, S., Hizel, L. and Bennett, D., 2012. The natural history of cognitive decline in Alzheimer’s disease. Psychology and Aging, 27(4), p.1008-1017.