Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Paula C. Bickford, Ph.D.

Committee Member

Kevin Nash, Ph.D.

Committee Member

Laura Blair, Ph.D.

Committee Member

Thomas Taylor-Clark, Ph.D.


Aging, Fractalkine, Microglia, Neuroinflammation, CX3CL1, T cells


Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting about 1.5 million people in the United States with more than 60,000 people diagnosed each year. It is classically characterized by four major symptoms: tremor, postural instability, stiffness in joints, and slow movement (bradykinesia). Pathologically PD is characterized by up to 70% loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) of midbrain and accumulation of presynaptic protein called α-synuclein (α-syn) within dopaminergic neurons that extend to the striatum. This disrupts the nigrostriatal pathway leading to the motor symptoms seen in PD patients. Microglia, the innate immune cells of the central nervous system (CNS) play a major role in maintaining homeostasis in the brain and with age these cells become primed, displaying decreased phagocytosis and expression of the anti-inflammatory cell surface receptor, CX3CR1. CX3CR1, fractalkine receptor expressed on microglia, interacts with type 1 transmembrane protein CX3CL1 (Fractalkine) expressed by neurons. CX3CL1, on binding its receptor on microglial surface, reduces the pro-inflammatory cytokines expressed in activated microglia. Fractalkine can be expressed in two isoforms, a membrane bound form (mFKN) that can be cleaved by metalloproteinase ADAM10/17 to produce a secretable soluble form of fractalkine (sFKN). CX3CR1 plays a major role in synaptic plasticity and cognition. However, the exact role of sFKN and mFKN with regard to cognition and neurogenesis in the CNS is not completely understood. In our study, we have examined the role of sFKN and mFKN using CX3CL1-/- mice overexpressing either form of fractalkine using adeno-associated virus (AAV) and show that soluble form of fractalkine plays an important role in cognition, synaptic plasticity and neurogenesis.

Disrupting fractalkine signaling has been shown to be detrimental, with increased neurodegeneration observed in various animal models of neurodegenerative disorders. The level of endogenous of fractalkine decreases with aging. Loss in CX3CR1-CX3CL1 signaling has been shown to increase neuron loss and microglial activation in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Expression of sFKN but not mFKN rescued neuronal loss and decreased microglial activation in this model. Also increasing the endogenous level of fractalkine has been shown to be beneficial in rescuing neuron loss and decreasing microglial activation in 6-hydroxydopamine (6-OHDA) model of PD. In an α-syn overexpressing young animal model of PD, expression of sFKN is shown to rescue neurodegeneration. However, one of the major risk factors for developing PD is aging, a consideration that has been overlooked in these previous studies. To evaluate increasing endogenous levels of sFKN as a therapeutic strategy for treating PD, we examined the effect of increasing endogenous sFKN using AAV on neurodegeneration and microglial activation in an aged model of PD. We have shown that although sFKN rescues neurodegeneration in a young animal model of PD, increasing sFKN did not rescue the neuron loss in an aged PD model. Primary microglial cells isolated from young and aged animals showed differential response to fractalkine treatment in vitro to immune insults such as lipopolysaccharide (LPS). These data will add weight to the idea of using a combination of therapeutics targeting various pathways in treating PD, and the consideration of aging as a major contributor to therapeutic efficacy when screening potential treatments.

Apart from chronic activation of microglia, CD4 and CD8 T cells are found in postmortem human PD brains. The role of T cells in either neurodegeneration or neuroprotection in PD is not well understood. Previous research corroborates the neurodegenerative role of CD4 T cells in an MPTP mouse model of PD. To explore the role of T cells in the context of α-syn pathology, we overexpressed α-syn in nude (T cell deficient) and heterozygous nude (T cell competent) rats and observed the neurodegeneration, microglial activation, and infiltration of T cells. We have shown that the neurodegeneration and behavioral phenotype associated with α-syn expression is dependent on T cells, and the degree of dopamine neuron loss is dose dependently linked to the number of T cells that are present in the periphery. We have also shown that T cells move away from the site of damage with aberrant neuron loss in SNpc. These studies support the literature that T cells play a major role in accelerating dopamine neuron loss in PD patients, however the exact role and subtype of the T cells involved needs to be further explored.

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