Grant: Project Grant

Over the past decade, population studies have taught us that genetic risk factors play an important role in Alzheimer's disease (AD) susceptibility. Many of these genetic factors converge on proteins that play unique roles in immune cells of the brain, called microglia. Human genetics and mouse models are teaching us important things about the roles for microglia in the development of AD, but there are still many unanswered questions. Mouse models are critical for studying neurodegeneration, however, genes unique to humans pose a challenge since mouse models do not capture their impact. We have been studying a top genetic susceptibility factor for AD, which is an receptor on microglia, called CD33, that is divergent between mouse and man. We have discovered that a short and long isoform of CD33 play differential roles in microglia. Most significantly, the short isoform of CD33 plays a crucial gain-of-function role. Better understanding this gain-of-function role could open new and exciting avenues for treating neurodegeneration. This project studies the connection between CD33 isoforms and AD in three aims. In Aim 1, we will seek to understand how CD33 is connected with another important AD susceptibility factor, TREM2. In Aim 2, we will test hypotheses related to how the short isoform skews microglia to make them better at fighting disease. In Aim 3, we will uncover splicing factors required to generate the short isoform in cells and use a proof-of-concept model to study the beneficial effect of isoform switching as a therapeutic approach. Overall, this project will uncover new ways by which microglia are controlled in the context of Alzheimer's disease and open new targets for immune-targeting therapies that can favourably skew microglia into a more protective state.