| Neuroinflammation resulting from chronic reactive microgliosis is thought to contribute to age-related neurodegeneration, as well as age-related neurodegenerative diseases, specifically Alzheimer's disease (AD). Support of this theory comes from studies reporting a progressive, age-associated increase in microglia with an activated phenotype. While the underlying cause of this microglial reactivity is idiopathic, a popular therapeutic strategy for the treatment of AD is inhibition of microglial activation through the use of anti-inflammatory agents. While the effectiveness of anti-inflammatory treatment for AD remains equivocal, microglial inhibition is being tested as a potential treatment for additional neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Given the important and necessary functions of microglia, careful evaluation of microglial function in the aged and injured brain is a necessary first step in targeting better treatment strategies.;Recent evidence suggests that microglia may undergo cellular senescence in response to normal aging and other exogenous insults. To further investigate this possibility we evaluated the replicative potential of microglia following repeated peripheral nerve injury. We found that repeated challenge to the same pool of microglial cells, in the form of facial nerve crush injury, results in decreased cell proliferation in rats 3, 4 or 5 days after axotomy. Concomitant with decreased mitotic potential, microglia challenged by multiple nerve injuries exhibited an altered immunophenotype characterized by increased expression of macrosialin, a macrophage marker known to be upregulated in the aged brain. To investigate normal macrosialin expression in the facial motor nucleus, we analyzed protein immunoreactivity in aged and young rats following a single facial nerve injury. We determined that macrosialin is not expressed by activated microglial cells in the facial nucleus of young rats after a single nerve injury, but rather is upregulated in response to aging in both injured and uninjured nuclei. These results suggest that macrosialin is a marker of aged microglial cells. Taken together, the diminished proliferative response concomitant with macrosialin expression seen in response to repeated injury may be indicative of microglial senescence. Changes in microglial function resulting from a senescent cellular phenotype may be detrimental to brain homeostasis and act to exacerbate aging-related neurodegenerative disease or play a role in increasing the susceptibility to such degenerative conditions. These studies provide an impetus for further investigation into the causes and effects of microglial senescence. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)... |
