Grant: Project Grant

Alzheimer's disease (AD) is a debilitating neurodegenerative disease. Despite the enormous efforts, we still do not understand the origins of AD. This lack of knowledge translates to the inability to effectively treat patients suffering from the plethora of pathologies associated with the disease, let alone a preventative. Keys to better understanding AD and developing new treatment strategies may lie in genetic factors that correlate with AD-susceptibility, which have much to teach us about brain homeostasis. Of particular interest are genetic factors related to genes expressed in immune cells of the brain called microglia. Microglia play many roles in the brain with the most well characterized being the removal of unwanted matter. This removal is an orchestrated event with specific receptors on microglia that guide this process known as phagocytosis. Curiously, several of the recently-emerging genetic factors correlating with AD-susceptibility are receptors in microglia that regulate phagocytosis. Accordingly, it has been proposed that an altered phagocytic ability by microglia could be a key element in AD-susceptibility. However, due to the complex role(s) played by microglia in AD, there are still many unanswered questions. One of the aforementioned genetic factors is CD33, a receptor on microglia that is a sugar-binding lectin. Two different versions (alleles) of CD33 are present in the human population with the rare allele correlating with protection from AD. It is of great interest to discover precisely how this protective controls microglia compared to the common risk allele of CD33. This project aims to elucidates the roles for these CD33 alleles by studying them in the context of a mouse model of AD and their divergent abilities to regulate microglia.