Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Sean Cregan

Abstract

The persistence of neural precursor cells (NPCs) in distinct niches of the adult brain and spinal cord provides an important opportunity for regeneration in the affected nervous system. In the adult brain, neural precursor cells (NPCs) generate new neurons that can be integrated into the CNS circuitry to replace damaged or lost neurons, and contribute to learning and memory processes. Deregulated neurogenesis has been observed under both acute and chronic neurological conditions including stroke, Alzheimer’s disease, and Parkinson’s disease. The extent to which neurogenesis contributes to brain repair is severely limited by the neuroinflammatory processes associated with these neurodegenerative conditions. During injury, microglia, the CNS resident immune cells become activated and produce a number of anti- and pro-inflammatory factors that can modulate neurogenesis and survival of NPCs. The goal of this study was to identify mechanisms of NPC apoptosis induced by microglia-derived cytokines. Using a conditioned media model, we have identified that activation of the TNFα, IL-1β and Fas signaling pathways induces death of NPCs via the intrinsic pathway of apoptosis in vitro. TNFα activates Puma and NPC apoptosis via an NF-κB-dependent mechanism. Activation of the IL-1β pathway, by microglia-derived or rIL-1β induces cell cycle arrest and apoptosis via p53-dependent upregulation of p21 and Puma. IL-1β can also induce an increased expression of Fas via an NF-κB-dependent pathway. Fas signaling in NPCs also culminates in activation of Puma and induction of mitochondrial-dependent apoptosis of NPCs. Puma appears to be a dominant regulator of cytokine-induced NPC apoptosis in vitro, as well as in an in vivo model of spinal cord injury. This study implicates microglia-derived TNFα and IL-1β as potent inducers of the BH3-only protein Puma through activation of the NF-κB and p53 pathways, respectively. Furthermore, these findings provide novel molecular targets to improve the survival of both endogenous and transplanted NPCs in regenerative therapies for acute and chronic neurological conditions.


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