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Faculty Profile: Leah Cuddy, PhD, research assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Behavioral Neurology

Leah Cuddy, PhD, is a research assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Behavioral Neurology. Her research aims to improve the understanding of how genetic variants increase Alzheimer’s disease risk and lead to neurodegeneration and neuroinflammation in patients.

What are your research interests? 

My research focuses on understanding the molecular mechanisms underlying Alzheimer’s disease pathology by studying risk-associated Alzheimer’s rare variants. Specifically, I am interested in better understanding how angiotensin-converting enzyme genetic variants increase Alzheimer’s risk and lead to neurodegeneration and neuroinflammation in the brains of Alzheimer’s patients. The substrates and physiological functions of ACE1 are complex and the mechanism by which ACE1 mutations are involved in Alzheimer’s pathogenesis is unknown. However, FDA-approved medications that target ACE1 exist for the treatment of hypertension, and my work could provide insight as to whether these drugs could potentially prevent or treat Alzheimer’s disease. Additionally, I am interested in elucidating mechanisms that disrupt protein clearance pathways in neurodegenerative disease and lead to the aggregation of pathological proteins, such as amyloid-beta and alpha-synuclein. I use transgenic mouse models, cell lines and human induced pluripotent stem cell derived neurons to investigate these questions. 

What is the ultimate goal of your research?  

The overall goal of my research is to gain an in-depth understanding of how rare genetic mutations lead to Alzheimer’s pathogenesis. This will lead to the identification of mechanisms that aid the development of novel therapeutic strategies for Alzheimer’s disease. Specifically, by studying rare variants of ACE, I hope to determine the physiological function of ACE1 in the brain and how altering ACE1 function increases the risk of Alzheimer’s disease.

How did you become interested in this area of research?

I became interested in Alzheimer’s disease research during my undergraduate degree at Western University in Canada. I was enrolled in an introductory course on neurodegenerative diseases that was taught by my eventual graduate advisor, and I learned about the very limited pharmacological treatment options for Alzheimer’s disease. Around the same time, I was involved in volunteer service for local Alzheimer’s outreach programs in the community. This allowed me to see the struggles of patients and caregivers and provided me with great insight into the translational impact of Alzheimer’s research.  

What types of collaborations are you engaged in across campus (and beyond)?

I am engaged in several collaborative research projects as part of the Vassar lab at Northwestern. We work closely with Dr. Rudy Tanzi, who directs the Alzheimer’s Genome Project. We also work with Dr. Dmitry Prokopenko at Massachusetts General Hospital toward investigating ACE genetic variants in Alzheimer’s disease. At Northwestern, we work regularly with Dr. Jeff Savas on proteomics-based studies. I also frequently collaborate with Dr. Joe Mazzulli, and we are currently working on a project investigating the impact of farnesyltransferase inhibitors on lysosome dysfunction in Alzheimer’s disease.

Where have you recently published papers?

I have most recently published papers in Science Translational Medicine and Neuron. I have also published a protocol in STAR protocols from Cell Press on the analysis of lysosomal hydrolase trafficking and activity in human induced pluripotent stem cell derived neuronal models. 

Who inspires you? Who are your mentors?

I have been very fortunate to work with many inspirational and supportive mentors over the years. My graduate advisor, Dr. Jane Rylett, and my post-doc mentors, Dr. Robert Vassar and Dr. Joe Mazzulli, have played a major role in helping to shape my career and develop my skills as a scientist. In addition, I am lucky to have worked with many excellent students and colleagues here at Northwestern whom I am able to refer to for any questions, guidance or support.