In line with the projects in the Fleming APOE consortium, this project will investigate APOE’s influence on the immune system, but on a more comprehensive level. Given the many immune cells and pathways implicated in AD and influenced by APOE, Dr. Wellington aims to construct an in-depth picture of the changes caused by APOE with age and how different factors influence those changes. Her preliminary data identify a highly novel role for APOE on immune checkpoint regulation. Three sets of mouse models with human APOE are commonly used across the APOE field. As the most historical model is distributed by Taconic Biosciences only to select investigators, two additional models have been created that have broad accessibility. One of these newer models is distributed by Jackson Laboratories, while CureAlz distributes the other. Direct, comprehensive comparisons of APOE models are needed. As part of this project, Dr. Wellington will perform such a comparison of CureAlz and Jackson Laboratory mice, helping to validate the two sets of models and identify key differences in immune profiling during aging between them that will help the field select and use the more appropriate model. This ambitious project will not only help build our understanding of APOE’s influence on immune checkpoints but also build a repository of critical information about the most accessible APOE mouse models in the AD field.
Dr. Wellington’s team proposes three aims in this project. In the first, they will examine how the expression and genotype of APOE interact with aging to influence immune checkpoint regulation in the CureAlz & Jackson Laboratories’ APOE3/3, APOE4/4, and APOE-deficient mice, along with their respective controls. Dr. Wellington will measure the levels of approximately 270 plasma proteins in each APOE model to map the changes occurring in these mice on the inflammatory and immune levels. The second aim is to explore how amyloid or tau pathology influences the plasma profiles of these models. The final aim will investigate how lipids bound to APOE influence plasma protein levels. One of APOE’s primary functions is to transport lipids throughout the body. However, APOE can perform other roles even while carrying those lipids, and the lipids themselves can influence how APOE functions in those roles.
