Describing the roles of myeloid cells in the compartmental degeneration of retinal ganglion cells in the neurodegenerative disease glaucoma

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Title Describing the roles of myeloid cells in the compartmental degeneration of retinal ganglion cells in the neurodegenerative disease glaucoma
Publication Type dissertation
School or College School of Medicine
Department Neurobiology & Anatomy
Author Breen, Kevin Thomas
Date 2015-12
Description The role that myeloid innate immune cells play in neurodegeneration has long fascinated researchers because of the apparent changes of these cells found in all neurodegenerative diseases. However, it has become clear that the different parts or compartments of a neuron that traverse different anatomical environments degenerate at different times. Since there are myeloid cells around all of these neuronal compartments, answering the question of how myeloid cells impact the process of compartmentalized neurodegeneration is challenging. Further complicating this question is the fact that these cells can rapidly change their morphology and function in a process termed activation. In these activated states, myeloid cells have the capacity to regulate many aspects of neuronal damage and repair. Lastly, these myeloid cells are derived from different lineages that may play different roles in neurodegeneration. Many authors have manipulated myeloid cells by loss of the receptor (CX3CR1) for the chemokine fractalkine and arrived at contrasting and context-dependent results even within models of the same neurodegenerative disease. Few studies have examined loss of fractalkine signaling in multiple compartments and even fewer have collected these data for each animal. Therefore, it remains unknown how loss of fractalkine signaling affects compartmentalized neurodegeneration. Since the chronic mouse model of glaucoma, the DBA/2J, grants easy access to different degenerating retinal ganglion cell (RGC) compartments, it is an ideal system to iv determine how myeloid cells affect neuronal compartmentalized degeneration. The DBA/2J also features changes to myeloid cells, including microglial activation as early as 3 months and macrophage infiltration at 10 months. We generated DBA/2J mice lacking CX3CR1, and determined that this differentially affected RGC compartmentalized degeneration by increasing numbers of RGCs with a marker of disrupted axonal transport while not affecting RGC transcriptional dysregulation or optic nerve degeneration. Loss of CX3CR1 did not increase microglial activation overall but increased macrophage infiltration. However, numbers of infiltrating macrophage did not correlate with RGC pathology. We found that early microglial activation was composed of resident microglia and that high levels correlated strongly with later optic nerve degeneration. All together, these data implicate the resident microglia in disease progression in neurodegeneration.
Type Text
Publisher University of Utah
Subject MESH Retinal Ganglion Cells; Glaucoma; Neurodegenerative Diseases; Myeloid Cells; Microglia; Optic Nerve; Optic Disk; Macrophage Activation; Chemokine CX3CL1; Axonal Transport; Synapses; Signal Transduction; Apoptosis; Microglia; Retina; Neurotoxicity Syndromes
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Describing the Roles of Myeloid Cells in ther Compartmental Degeneration of Retinal Ganglion Cells in the Neurodegnerative Disease Glaucoma
Rights Management Copyright © Kevin Thomas Breen 2015
Format application/pdf
Format Medium application/pdf
Format Extent 12,531,539 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6894f6p
Setname ir_etd
ID 197341
Reference URL https://collections.lib.utah.edu/ark:/87278/s6894f6p
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