Shannon MaCauley-Rambach
Shares Her Journey Since
Receiving One of the 2015
New Vision Investigator Awards

In 2015, I had the privilege of participating in the Charleston Conference on Alzheimer’s Disease and accepting a New Vision Award. The goal of my proposal was to understand how changes in metabolism impact the progression of Alzheimer’s disease (AD) and whether targeting metabolic dysfunction was a viable therapeutic approach. Using rodent models with Alzheimer’s-related pathology, this project had a three pronged approach. First, our goal was to establish whether changes in cerebral metabolism alter brain excitability and amyloid-beta (Aβ) levels, a hallmark of Alzheimer’s disease pathology. In our publication in Journal of Clinical Investigation, we demonstrated that elevations in peripheral glucose levels increased glucose metabolism and excitability in the brain. This, in turn, increased Aβ production, suggesting a direct link between metabolic alterations and Alzheimer’s disease pathogenesis. Through these initial studies, we hypothesized that ATP sensitive, inward rectifying potassium (K ATP ) channels on neurons act as a metabolic sensor to couple changes in cerebral metabolism with brain excitability and Aβ production. Therefore, the second goal of my New Vision award was to determine if K ATP channels were necessary for hyperglycemia-dependent changes in Aβ. Using transgenic mice lacking K ATP channel activity, we found these channels are indeed necessary for glucose dependent changes in Aβ. Not only did these mechanistic studies define the relationship between metabolic alterations and AD pathogenesis, but it identified a potential therapeutic target in Alzheimer’s disease. Therefore, the last part of my proposal was to explore whether the FDA approved, K ATP channel antagonist, glyburide, could alter Aβ-related pathology in mice. We found that systemic delivery of glyburide reduced amyloid plaque burden by altering excitability at the neurovascular unit. Findings from this work were presented at national and international conferences, including Keystone Conference, AD/PD, American Diabetes Association, Society for Neuroscience, and BRAIN & BRAIN PET, and manuscripts detailing our observations are in preparation and under review.

Not only did the New Vision award give me the opportunity to explore a high risk, high reward project, it laid the foundation for my career as an independent investigator. First, the preliminary findings from this project served as a launch pad for subsequent funding from the NIH and small foundations, including a K01 from the NIA entitled, “Effects of hyperglycemia on neuronal activity, cerebral metabolism, and Aβ levels”; a newly awarded R01 from the NIA entitled, “The metabolic interplay of sleep and Alzheimer’s disease”; and a Bright Focus Foundation research grant entitled, “K ATP channel inhibition as a modifier of tau pathology in Alzheimer’s disease”. Second, it gave me the opportunity to establish my own laboratory focused on metabolism, excitability, and Alzheimer’s disease. In 2017, I left Washington University in St Louis, MO to start a tenure track position at Wake
Forest School of Medicine in Winston Salem, NC. At Wake Forest, the NIH-funded, Alzheimer’s Disease Research Center focuses on metabolic and vascular risk factors in Alzheimer’s disease, making it an ideal place to establish my laboratory and expand my research program. Although starting a lab is challenging, I enjoy the balance of research, education, and mentorship; especially mentorship! I am very fortunate to have a tremendous team of PhD, Master’s, and postdoctoral trainees to help guide the
work in our lab. Lastly and perhaps most importantly, CCAD and the New Vision award gave me the opportunity to build a collaborative network which has been instrumental in my success as an early stage investigator. Whether it be the unwavering support from colleagues, sharing of reagents, or building collaborations, the relationships that I built through CCAD are undoubtedly a key component of my success. Therefore, I’m grateful for the opportunities CCAD has provided to date and look forward to what lies ahead as we seek to better understand and offer treatment strategies for Alzheimer’s disease.