Adam Mullis

Research/Areas of Interest

I am working on developing human 3D brain tissue models of Alzheimer’s disease (AD) to compare differences in pathobiology between cortical and cerebellar brain regions. AD is a progressive neurodegenerative disease that is the most common cause of dementia. To date, no disease-modifying therapies exist (with the possible exception of the controversial monoclonal antibody aducanumab). Many preclinical disease modifying candidates have been identified, but to date all have failed in clinical trials. This collective translational failure is due in large part to a lack of physiologically relevant preclinical models for studying AD pathogenesis or testing such candidates. Most in vitro testing is performed in monolayer neuronal cultures, which lack the high cell density, 3D organization required for accurate recapitulation of tauopathy phenotypes. Additionally, most of these models rely on familial AD (fAD) patient-derived cell lines or viral-induced overexpression of fAD mutations, while fAD represents only approximately 5% of all AD cases. In my research, I plan to generate cerebellar and cortical 3D tissue models using patient-derived induced pluripotent stem cells. Using biological and chemical insults in healthy tissues, I will investigate possible differential plaque and tangle clearance capacities between cerebellar and cortical cells. Then, using familial and sporadic AD patient-derived tissues, I will investigate differences in plaque and tangle formation between cerebellar and cortical tissues. These studies will allow us to test the hypothesis that cerebellar environmental factors are key contributors to the suppressed plaque and tangle phenotype in the cerebellum, and provide a better understanding of the relative neurotoxic susceptibilities of cerebellar and cortical neurons in AD.