Assignment #1 Name: Elena Bricker Due Date: Monday January 29th, 11:59pm. Submit assignment as word doc via course blackboard site.
Read the scientific review paper titled, “Trafficking and Proteolytic Processing of APP” by Haass et al. 2012 which is posted on blackboard. · Assigned pages: 1-7 · Excluded: “Cellular trafficking of APP” and paragraph titled “Familiar Alzheimer Disease – Associated Mutations within the APP Gene Affect Ab Generation and Aggregation”.
In your own words, answer the following questions. 1- What is the major, fundamental difference between amyloidogenic and non-amyloidogenic APP processing? What is the mechanism by which this difference arises? The amyloidogenic pathway cuts APP using beta-secretase and gamma-secretase to isolate amyloid beta. In the non-amyloidogenic pathway, alpha-secretase cuts APP in the middle of Ab. 2- During amyloidogenic processing, the protein APP is cleaved into several fragments. What are they? Beta-secretase cleaves APP into APPsband C99.
Gamma-secretase cleaves C99 into Ab and AICD. 3- Why is alpha secretase protective from the formation of the beta-amyloid peptide? Alpha secretase cleaves in the middle of the Ab which leaves the APPsa and a C89, making the Ab segment incomplete. In the anti-amyloidgenic pathway, the g-secretase cleaves in the same location, leaving the incomplete Ab, p3.
4- Based on the mechanism of beta-amyloid production, one might reasonably conclude that beta-amyloid production can be avoided if the amyloidogenic pathway is halted. However, this may have serious consequences as discussed in the paper. How so? Explain + summarize the physiological and pathological role of BACE (i.e.
, what does BACE do that is beneficial vs non-beneficial?). Consequences of targeting and preventing BACE from working include impairment of memory, voltage-gated sodium channels, myelination (production of myelin sheath), and the function of several other substrates. 5- Considering the amyloidogenic and non-amyloidogenic pathways, what other molecular players could scientists target to prevent beta-amyloid production in Alzheimer’s disease? Explain why the molecular player of your choice would create a novel and effective therapy for Alzheimer’s disease? As the article mentioned, in research using animals, increasing the production of alpha secretase lowers the amount of Ab.
Alternatively, you could inhibit gamma-secretase from working, which would leave the C99 section intact and thus leave Ab uncleaved.