Genomic Editing to Elucidate CD33 Function

Steven Estus, PhD University of Kentucky Research Foundation


About 70 percent of the hereditary risk of acquiring Alzheimer’s disease is due to differences in DNA sequences between people. We have identified how one of these DNA sequence variations changes gene expression to reduce Alzheimer’s risk. The action of the DNA sequence difference accounts for a modest 15 percent decrease in functional gene expression. Remarkably, an inhibitor of this gene has already been in clinical trials for leukemia, and will be tested here for its ability to act similarly to the DNA sequence variation, resulting in a potentially protective effect.

Project Details

Our short-term goal is to understand how a hereditary difference in a gene called CD33 acts to reduce the risk of Alzheimer’s disease (AD). Our longer-term goal is to translate this information into a drug that mimics this protective effect, and thereby reduces AD risk. CD33 encodes a protein that is thought to inhibit the cells that are the “janitors” of the brain. These cells, termed microglia, digest cellular debris as well as the amyloid protein that appears to cause AD. We recently found that the hereditary difference in the CD33 gene acts by increasing the proportion of an unusual CD33 form, termed D2-CD33. In work supported by BrightFocus, we are generating microglia that make normal CD33 or D2-CD33 to understand how D2-CD33 alters microglia function to reduce AD risk. Our hypothesis is that CD33 but not D2-CD33 inhibits the janitorial function of microglia. The main finding that sets our work apart from the field has been our recognition that increased D2-CD33 relative to CD33 explains how the hereditary difference in CD33 reduces AD risk. Hence, drugs which increase D2-CD33, or decrease CD33, would be expected to reduce AD risk. We propose to compare alterations in D2-CD33 and CD33 expression as a critical step in translating our findings into an AD-preventive agent.