AAV Vectors for Oligodendrocyte Precursor Cells (OPCs)

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.

Grant Number: 1R61AG094645-01
NIH Institute/Center: NIH
Principal Investigator: DWIGHT BERGLES