Tomorrow and in the following days, you will likely see stories popping up in media across the country about an important discovery made at UT Southwestern concerning Alzheimer’s. But FrontBurner is breaking the story. Working on nothing but a thin rumor, we dispatched intern Jessica Norsch to uncover the truth. Jessica’s last day with the magazine was earlier this week. But that didn’t stop her from filing this report–and breaking national news. (Editor’s note: save for one or two minor changes I made, Jessica’s copy comes to you exactly as it came to me. Look for her to go places.)
“Unprecedented mechanism of biochemistry” could be important step in curing disease.
By Jessica Norsch
After nearly four years of study at UT Southwestern Medical Center, researchers have determined a prominent factor in the development of Alzheimer’s disease. Their findings will appear in the respected journal Cell. It was rumored that they had isolated a significant protein called nicastrin that was believed to aid in the progression of the disease. My last mission as a D intern was presented: find out what it was and if, in fact, the rumors were true. Phone calls where made, years of research in cell biology were read (and read again), and the interview took place.
First and foremost, the research was focused on the production of a kind of protein found in the brain called beta-amyloid. The study behind this protein dates back to 1906 when Dr. Alois Alzheimer discovered changes in the brain tissue of a woman who died of a mysterious mental illness. The tissue contained irregular clumps (beta-amyloid) that eventually led to signs of dementia and finally, what we know today as Alzheimer’s disease. While the protein doesn’t pose a threat on its own, it is the accumulation that leads to the plaque-like buildup that threatens the onset of the disease. But because the presence of the protein is mandatory, Southwestern researchers had to isolate the protein and break down its cellular makeup in order to fully understand how to manipulate it. Dr. Gang Yu, assistant professor in the Center for Basic Neuroscience and of Cell Biology and senior author of the study, cites the findings as an “unprecedented mechanism of biochemistry.”
The researchers used cultured human and mouse cells to isolate the beta-amyloid protein, which led to their ability to single out the role of another key protein, nicastrin. Aware that not everyone understands the common terminology of cellular biology, Dr. Yu explained the newly discovered role of nicastrin during our meeting. The nicastrin protein is also a part of an enzyme called gamma-secretase, which is wedged in the cell’s membrane. These two together, gamma-secretase and nicastrin, have previously been thought to make up a key component in the development of another protein called amyloid-beta. Nicastrin binds to the amyloid-beta proteins, one in particular called amyloid precursor protein (APP), and then guides it to the gamma-secretase where the APP is then split in two; one half remains inside the cell and the other travels outside. The half that travels outside the cell eventually clusters and forms the plaque, or the resulting protein beta-amyloid, that is thought to cause Alzheimer’s. Now that the role of nicastrin has successfully been identified, Southwestern researchers are anxious to learn how to block the splitting of APP. The current theory is that if APP never attaches to nicastrin, APP remains whole and harmless, avoiding the creation of the plaque causing beta-amyloid. Dr. Yu told me that while this is not a cure, “the next generation of therapy mainly deals with this pathway.” Preventing one small split of APP could mean a significant leap in the ongoing fight against Alzheimer’s.
Dr. Yu has been working at Southwestern since 2001, but his research extends years before his arrival in Dallas. He has been awarded the Thomas O. Hicks Scholar in Medical Research and credits his colleagues with the latest findings as well. One contributor that stands out is Sanjiv Shan, lead author and student research assistant (yes, student) in Dr. Yu’s lab. When asked if it was common for a student to play such a prominent role in a discovery, Dr. Yu smiled and said, “He is a student who can really think and look at a question and can work on it. I would consider him one of the best.” He then went on to comment about how Sanjiv’s dedication sometimes leaves him pulling out his travel pillow and nodding off for a quick nap in the lab, then returning to his long hours of research.
While Sanjiv made significant contributions to the substantial findings, Dr. Yu also noted the assistance of the following: Drs. Sheu-Fen Lee and Katsuhiko Tabuchi, assistant instructors; Drs. Yi- Heng Hao and Cong Yu, postdoctoral researchers; Dr. Thomas Sudhof, director of the center; Quincey LaPlant, Medical Scientist Training Program student; Dr. Charles E. Dann III, postdoctoral researcher in biochemistry, and Dr. Hayden Ball, assistant professor of biochemistry. The study was also supported by the National Institutes of Health, the Welch Foundation, the American Health Assistance Foundation, the American Federation for Aging Research and the Alzheimer’s Association.
That concludes our cellular biology lesson for today. Rumor confirmed. Mission accomplished. –with reporting by Gable Vines