UC San Diego

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease that is characterized by the formation of Amyloid-beta(Aβ) plaques in the brain. My project focuses on Amyloid Precursor Protein (APP) processing which generates Aβ. APP has a cholesterol-binding domain (Beel et al., 2010). We used CRISPR-CAS9 to induce mutations that abolish APP- cholesterol binding in stem cells which were then differentiated to neurons. In the mutants that lack cholesterol binding, we observed decreased Aβ 42, increased β-CTF, and no change in APP full-length levels, when compared to wild type (WT) at baseline. In wild-type neurons treated with atorvastatin, we saw decreased Aβ 42, sAPPβ, and β-secretase, increased APP full length, and no change in β-CTF, Presenilin 1, and Presenilin 2 levels. Similar changes were observed in atorvastatin-treated mutants, however, the decrease in Aβ 42 and the increase in APP full length was blunted compared to atorvastatin treated wild-types. Our finding indicates that cholesterol regulates APP processing through mechanisms that are more complex than previously hypothesized. This observation can provide de novo insights to the relation of cholesterol and APP processing, with relevance to AD pathogenesis.