Protein aggregation can be held responsible for most neurodegenerative diseases as it is the cause of death of neurons. These aggregated proteins are heavily composed of beta pleated sheets (Hoshino et al., 2014). Alzheimer’s disease can be classified as a tauopathy, which means that the disease is caused by aggregation of the tau protein both intracellularly and extracellularly. Although the aggregation of proteins is believed to be initiated spontaneously, some factors may increase an individual’s risk of a neurodegenerative disease. One of these factors is a family history of the disease because the concentration of the protein in these individuals is higher than most. With increased concentration of the protein comes increased risk of protein aggregation. Another factor is hyperphosphorylation which is seen in tau protein aggregation (Ross and Poirier, 2004). Misfolded proteins also play a major role in the disease process. Because protein structure determines protein function, it can be assumed that disrupting the protein structure disrupts the protein function leading to disease. Under normal circumstances, chaperone proteins assist in the folding of proteins to prevent misfolding and protein aggregation. Because chaperone proteins affect the folding of proteins, they play a major role in protein aggregation and anti-aggregation. When proteins are misfolded, chaperones work to refold the proteins correctly so that they can regain their correct function (Hoshino, 2014). Perfecting the use of chaperone proteins has the potential to correct protein misfolding before the disease process is irreversible.

            ProSAAS is a commonly occurring neuroendocrine protein in neurons that helps to prevent protein aggregation by inhibiting prohormone convertase 1/3. The levels of proSAAS and prohormone convertase 1/3 in the body are not always directly related, which presents the possibility of proSAAS having multiple functions. Since proSAAS has successfully treated diseases including Alzheimer’s disease, Pick’s disease, and parkinsonism-dementia complex, researchers have deemed proSAAS treatments effective on taupathies. This study is attempting to replace the current use of 7B2 with the use of proSAAS to treat Alzheimer’s disease. ProSAAS is a more viable option for the treatment of Alzheimer’s disease because it is more readily available. The human body naturally has much more proSAAS than 7B2. Researchers made the connection between proSAAS and 7B2 having similar functions because they both colocalize with amyloid proteins (Hoshino et al., 2014). The success of this experiment would prove that the true cause of Alzheimer’s disease is the aggregation of tau proteins. This can be concluded because naturally occurring proSAAS functions as an anti-aggregant of tau proteins. This breakthrough would not only affect research of Alzheimer’s disease, but it would also lead to discoveries in other tauopathies such as Pick’s disease. The goal of researchers in this study is to replace the current use of 7B2 in Alzheimer’s patients with the use of proSAAS in order to provide a more effective and readily available treatment. Researchers are using proSAAS to attack the root of the problem of Alzheimer’s disease rather than just treat the symptoms that Alzheimer’s patients experience (Hoshino et al., 2014).

            In this study, researchers obtained brain tissue from a seventy-three-year-old with Alzheimer’s disease. The first step of the process was labeling markers in the brain tissue for proSAAS and Alzheimer’s disease. This was done by looking at the immunoreactivity in the brain. Mice brains were also used in this study to provide more research tools. The same markers were identified in the mice brains. After these brain samples were prepared, the proSAAS plasmid was prepared. The proSAAS was His-tagged using GC-rich PCR. The researchers confirmed that they had correctly cloned the plasmid using sequencing (Hoshino et al., 2014). The proteins were also prepared and stored at -80°C. The in vitro fibrillation assays were then performed, and the plasmids were treated with some form of proSAAS or carbonic anhydrase. Images were taken of these samples and how the different substances affected the tissues differently. A dot blot analysis was also done to give more detail on how each tissue reacted to the different treatments (Hoshino et al., 2014). Researchers also took a separate sample of mouse brain tissue and put it through co-immunoprecipitation and looked for signs of proSAAS. After some time, researchers treated the cells with oligomers, proSAAS, or a negative control. These samples were then observed under the microscope (Hoshino et al., 2014).

            In both the human and the mice models, the proSAAS would aggregate wherever the amyloid protein was. This was the result that researchers were looking for in this study. These results show that proSAAS will function as the 7B2 drug did. When tested, the control brain and the brain with Alzheimer’s disease had the same levels of proSAAS; however, the proSAAS in the brain with Alzheimer’s was immunoreactive. The stains show that these results are consistent in both dense and lose tissues. The figures also suggest that proSAAS directly interacts with beta-amyloid. Researchers also learned that proSAAS prevents or shortens the formation of misfolded proteins. Although the drug can prevent the formation of misfolded proteins, it cannot destroy the pre-existing proteins (Hoshino et al., 2014).

            Figure 1 proves that proSAAS and the amyloid plaque colocalize. The stains show results from both a healthy control patient and an Alzheimer’s disease. In the samples of patients with Alzheimer’s disease, the proSAAS and beta-amyloid strongly co-localized. In the control brain, no immunoreactivity was observed (Hoshino et al., 2014). This figure proves that the study was successful in using proSAAS as a treatment for Alzheimer’s disease. ProSAAS performed the same function as 7B2 which was the desired outcome of this study. With proSAAS being more readily available and naturally produced, this has the potential to be a much better treatment for Alzheimer’s disease that 7B2.

            In conclusion, this study has shown how proSAAS can act like a chaperone protein to prevent the aggregation of misfolded proteins. Researchers showed that these methods are effective in vitro. The colocalization of proSAAS with the amyloid protein proves that the use of proSAAS can prevent or slow down the aggregation of proteins that cause cell death which in turn causes Alzheimer’s disease (Hoshino et al., 2014).

References

Hoshino, A., Helwig, M., Rezai, S., Berridge, C., Eriksen, J.L., and Lindberg, I. (2014). A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer’s disease. Journal of Neurochemistry 128, 419-430. 

Ross, C.A., and Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nature Medicine 10, S10-S17.