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<p>Huntington’s Disease (HD) is an inherited, progressive, fatal, and late-onset neurodegenerative
disorder. Its neuropathogenesis is characterized by selective loss of medium spiny
neurons (MSNs) in the striatum and cortical neurons in the cortex. It is caused by
an expansion of CAG repeats in the exon-1 of IT-15 gene, which results in a mutated
polyglutamine domain in the huntingtin protein (HTT) (Collaborative, 1993). The mutation
that causes HD was identified almost thirty years ago, yet the ultimate cause of neuron
death is still uncertain. This dissertation is based on the hypothesis that monocytes
infiltrate the brain of late stage HD patients and drive neuropathogenesis. To test
this hypothesis, I developed a novel hybrid brain-slice experimental model in which
human monocytes (MO) isolated from HD and non-disease control patients (CTRL) are
engrafted into living postnatal striatal brain tissues prepared from neonatal rats.</p><p>In
the first set of experiments, the inflammatory response of stimulated HD and CTRL
MO were tested. HD MO exhibited an increased inflammatory response demonstrated by
increased production of cytokine IL-10. Furthermore, a late-stage HD patient exhibited
an increased production of multiple cytokines, including IL-10. </p><p>The second
set of experiments utilized a brain-tissue based model to measure the impact of engrafting
HD MO on MSN health. In brain slices engraftment with HD MO, there was a decrease
in the number of healthy MSNs. A further experiment revealed that stimulating MO prior
to their engraftment differentially influenced the survival of MSNs depending on whether
the MO came from HD or CTRL patients. Measurement of cytokine production from these
unstimulated/stimulated engraftment experiments revealed a trend for increased cytokine
production in samples taken from a moderate stage HD patient. </p><p>The third set
of experiments assessed the ability of HD MO to influence the endogenous macrophages
within the brain slice tissue, microglia. MO engraftment, independent of its genotype,
altered microglia morphology within brain slices. Further results from these experiments
demonstrated that the presence of HD MO increased microglial density and upregulated
their phagocytosis of MSNs. While the mechanisms underlying these multicellular interactions
remain to be determined, it is possible that such an increase in phagocytosis could
lead to the observation of fewer healthy MSNs as quantified in the second set of experiments.
</p><p>Together, these three sets of experiments support the application of a novel
model to study neuropathogenesis and highlight that the genotype of infiltrating MO
has the potential to quantifiably alter intercellular interactions and neuronal health
in the context of HD.</p>
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