Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department


Major Professor

Kevin Nash, Ph.D.

Co-Major Professor

David Morgan, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Daniel Lee, Ph.D.

Committee Member

Edwin Weeber, Ph.D.


Alzheimer's disease, Fractalkine, Microglia, Neurodegeneration, Neuroinflammation


Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and the most common form of dementia. The hallmark pathologies of AD are extracellular aggregates of amyloid-beta, intracellular aggregates of microtubule associated protein tau and increased neuroinflammation. Current therapeutics offer only symptomatic relief and clinical trials investigating therapeutic benefits of non-steroidal anti-inflammatory drugs have yielded no positive results. Therefore, recent work has focused on immunomodulators, such as CD200 and fractalkine, as potential therapeutic targets for AD.

Fractalkine (CX3CL1; FKN) is expressed as a transmembrane protein with an N-terminal chemokine domain followed by a long, mucin-like stalk. FKN can signal as a membrane-bound protein or, upon cleavage, as a soluble ligand (sFKN). Upon binding its receptor, FKN reduces expression of pro-inflammatory genes in activated microglia.

Disrupting FKN signaling has been shown to exacerbate neurodegeneration in a number or neurodegenerative diseases. Relevant to this study, there have been conflicting reports on how FKN signaling affects AD pathology and whether a soluble FKN is beneficial or not. Here, we examine the ability of soluble FKN over expression to impact tauopathy and the resulting cognitive deficits in the rTg4510 mouse model of tauopathy, focusing on cognitive improvement after the onset of tau deposition. Furthermore, we explore the functional activity of proteolytic fragments of FKN on activated microglia in vitro to rectify the contradictory findings in the literature.

We observed that sFKN over expression can significantly reduce both soluble and insoluble phospho-tau in both a preventative and an early interventional study design. However, in animals with significant pathology and neurodegeneration we did not observe an impact of sFKN over expression on tau pathology. Interestingly, in these late stage animals we did observe an improvement in spatial learning and memory as well as a reduction in hyperactivity. This suggests that earlier intervention would likely be most beneficial in reducing tau pathology but in late stage AD FKN signaling can still have benefits on cognition, likely due to reductions in the inflammatory milieu.

Current publications suggest that different proteolytic fragments of FKN may have different functional signaling. Here we demonstrate that the this may be due to differences in receptor binding. sFKN (which includes the mucin-like stalk) exhibited a lower EC50 than the ckFKN (soluble chemokine domain), which leads to reduced functional efficacy of ckFKN at low concentrations. More interestingly, we also observed that high concentrations of FKN, regardless of cleavage variant, is ineffective at reducing pro-inflammatory activation of microglial and may in fact elicit a proinflammatory response. We hypothesize that FKN may signal through an alternative receptor at high concentrations, suggesting an as yet unidentified signaling pathway for FKN. Furthermore, we show that the ckFKN does not rescue pathology in the rTg4510 mouse, as sFKN does. These data may clarify conflicts in the literature and demonstrate that care must be taken with respect to in vitro and in vivo studies using FKN.

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