The Alternative Splicing of ApoER 2 in Alzheimer ’ s Disease

Over five million adults over the age of 65 currently suffer from Alzheimer’s disease (AD), a debilitating disease with no cure. Early diagnosis of AD allows for an increased ability to manage the disease, but diagnosis is limited by a lack of reliable AD biomarkers. While there is no singular cause, research has linked an isoform of ApoE to early onset AD, but recently more attention has been placed upon one of ApoE’s receptors, ApoER2. Like most genes, ApoER2 undergoes multiple alternative splicing events to create distinct mRNA isoforms. One Splicing event, exon 18 inclusion vs. skipping, creates two isoforms with opposing functions in reelin signaling, synaptic plasticity, and memory functions. We hypothesize that ApoER2 alternative splicing correlates with AD progression. Using cellular and animal models, and human samples, we found a disease state association between increasing AD severity and increased ApoER2 exon 18 skipping. We conclude that ApoER2 may play a role in regulating a pathway that is deregulated in AD. Acknowledgements This thesis would not have been possible without the support of a handful of individuals. First, I would like to thank Dr. Michelle Hastings for the opportunity to work in her lab; her mentorship throughout this process proved indispensable. I would also like to acknowledge Dr. Shubhik DebBurman for his never-ending support and guidance throughout not only this process but my entire experience at Lake Forest College. Thank you for constantly pushing me to achieve more than I knew I was capable of. Additionally, I would like to thank Professor Dawn AbtPerkins and Dr. Robert Glassman for working with me on a rushed time table to make this thesis possible. My research would not have been possible without those who previously worked on this project, including: Paige, Angela, etc. The support and guidance of Fran Jodelka, Mallory Havens, Alicia Case, Anthony Hinrich, Cidi Wee, Ashley Reich, Kate McCaffrey, and Alejandra Luna also allowed me to learn more than I could have hoped, and their ability to put up with my never-ending questions still astounds me. Lastly, I would like to thank those that have supported me throughout not only this endeavor by my entire life as well, my family. Without their support I would never have been able to get to this point in my life. I also need to thank my peers in the biology and neuroscience departments for helping me throughout the past few years and my friends in Delta Gamma Fraternity for their constant affection and ability to make sure I kept my sanity as I pushed myself to complete this capstone in my education.