AAV Vectors for Oligodendrocyte Precursor Cells (OPCs)

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary/Abstract: Glial cells perform crucial homeostatic roles in the CNS to maintain an environment where neural signaling and neural health can be sustained throughout the lifespan. Brain aging, injury, and disease place additional stresses on glia, which often undergo reactive changes to limit damage and promote repair. However, the distinct responses of glial cells to aging and disease, and the consequences of these phenotypic changes on normal homeostatic functions, are incompletely understood. Although most studies of glial cells have focused on astrocytes, oligodendrocytes, and microglia, the mammalian CNS also contains an abundant, highly dynamic population of glial progenitors termed oligodendrocyte precursor cells (OPCs). In adulthood, OPCs retain the ability to generate oligodendrocytes, producing new myelin sheaths in response to changes in life experience and restoring myelin lost through normal aging or destroyed by disease. Accumulating evidence indicates that OPCs do more than simply act as progenitors, as they migrate to sites of injury and contribute to barrier/scar formation, engulf axons and synapses to sculpt neural circuits, create and modify the extracellular matrix, and present exogenous antigens through MHC class I and II when exposed to inflammatory cytokines. In the context of Alzheimer’s disease (AD) pathology, OPCs exhibit hypertrophy and surround A plaques, placing them in a position to profoundly impact disease progression. Nevertheless, the consequences of these changes in OPC behavior and their impact on oligodendrogenesis are unknown, in part, due to a dearth of tools that allow selective manipulation of these cells in vivo. In this two-phase project, we will generate novel OPC-selective adeno-associated viruses (AAVs) and then use these vectors to test the hypothesis that reactive transformation of OPCs surrounding A plaques reduces plaque burden in AD model mice through Megf11 mediated engulfment. We will also explore how plaque formation alters glutamate signaling with OPCs, the only glial cells that have been shown to form direct synapses with neurons and impacts their ability to generate new oligodendrocytes. We will use innovative, state-of-the-art methodologies to accomplish these goals, including sensitive identification of DNA enhancer elements to limit gene expression to OPCs, in vivo selection of viral capsids that enhance OPC tropism, and rigorous brain-wide analysis of OPC targeting. In vivo monitoring of glutamate signaling and OPC behavior using time lapse two photon imaging will provide direct assessments of neurotransmission in peri-plaque regions. By establishing clear benchmarking and firm criteria for transitioning to the R33 testing phase of the study, we will develop new tools that provide lifelong access to OPCs for mechanistic interrogation and novel insight into the role of reactive OPCs in limiting AD pathology.