Developing peptidomimetics of secreted amyloid precursor protein-alpha (sAPPα) that confer neuroprotection and stimulate novel protein synthesis
FDA drug approval process takes years to reach manufacturing, development is 2-10 years, pre-clinical treatment another 3-6, clinical trails 6-7 years and finally FDA review, another 1-2 years. This a long process due to the safety concerns for releasing a new drug, with unseen side effects often occurring. This said a new drug that is treating a disease that has no treatment or no cure is fast tracked, shortening this time substantially. The point I am trying to make, is that Alzheimer’s disease has no cure, it has no treatment and by 2050 it is expected that 16 million in the US alone will be struggling with the disease. Any drug developed for Alzheimer’s disease would be fast tracked, nevertheless there are still no drugs available. Many proteins in the amyloid precursor protein (APP) pathway have been investigated to better understand Alzheimers disease. Secreted amyloid precursor protein alpha (sAPPα) is a candidate for drug design, it’s proven function include neuroprotection and eliciting neurone growth and proliferation. This study aimed to elaborate on the mechanisms of the sAPPα protein. Investigating if subsections of the sAPPα protein, RER and the 16mer have a similar level of functionality, specifically its neuroprotection. An additional aim is to investigate novel protein synthesis caused by sAPPα. This was done through a molecular technique SILAC (Stable Isotope Labelling of Amino acids in Cell culture) enabling us to identify a range of proteins that had altered levels of expression with the addition of sAPPα. My results showed that protein expression change over time when induce with sAPPα, with vastly different spectrum of altered protein expression at 6 and 12 hours. Some of the functions purposed to be effected by induction with sAPPα was RNA processing, DNA repair, glycolysis and cell growth and proliferation. There were proteins identified with a direct link to sAPPα, such a nicastrin and its role in 𝛄-Secretase. The protein analysis also brought new questions from which future SILAC experiments could be designed. Data was also analyzed for the subsections of sAPPα, showing that each induced a different spectrums of proteins, with some correlation observed between the RER/16mer with the full length sAPPα. The discovery of the sAPPη allowed an increase understanding and practice of biochemical techniques, but functional assessment is for further work.
Advisor: Tate, Warren
Degree Name: Master of Science
Degree Discipline: Biochemistry
Publisher: University of Otago
Keywords: Alzhiemers; sAPP(alpha)
Research Type: Thesis