Mechanisms for Alzheimer’s Disease-associated SORLA Mutations in Microglia and Neurons in AD Pathogenesis

Memory loss and mental decline associated with Alzheimer’s disease arise from neuronal impairment. Many genes associated with Alzheimer’s disease that were identified through genome-wide analysis represent genes that are mostly active in microglia, the innate immune cells in the brain. One Alzheimer’s disease risk gene, SORLA, is expressed in both neurons and microglia. This gene previously has been shown to reduce levels of the toxic amyloid beta peptide in cultured cells and mouse models of Alzheimer’s disease. SORLA can protect neurons from pathways that disrupt neuronal communication in the presence of amyloid beta. How SORLA influences neuronal protection in microglia remains unexplored. Various mutations within the SORLA gene have been identified in human Alzheimer’s patients. Studying these mutations has the potential to determine how altering SORLA function can disrupt neuronal communication. This research project will develop a model for mutant SORLA in neurons and microglia by integrating Alzheimer’s disease-associated SORLA mutations in embryonic human stem cells that will be differentiated into neurons and microglia. By analyzing how SORLA mutations can alter global gene activity, cellular function, and the cell’s response to amyloid beta in neurons and microglia, this research may be able to understand how alterations in SORLA can enhance Alzheimer’s disease risk.