Graduation Date
Fall 12-15-2017
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmacology and Experimental Neuroscience
First Advisor
Howard Gendelman
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative
disorder, second only to Alzheimer’s disease (AD). It is characterized by a
progressive loss of dopaminergic neurons along the nigrostriatal axis and the
formation of proteinaceous inclusions of alpha-synuclein (α-syn). Secondary to
the loss of dopaminergic neurons is a progression in motor and non-motor
symptoms. Motor symptoms are characterized by slowness in movement,
stiffness and tremor. Non-motor symptoms include depression, constipation,
sleep abnormalities and loss of sense of smell. The cause of disease remains
incompletely understood. However, age, genetics, environment, viral infection,
and interplay between the innate and adaptive immune system can contribute to
disease onset and progression. Currently, treatments are palliative, and no
known intervention to halt disease progression exists. Drug therapies employ
dopamine or a dopamine precursor that affect neurotransmitter signaling while
showing no effect on the neurodegenerative process. Nonetheless, the available
therapies improve walking, movement and tremor debilities. Therefore, it remains
essential that therapies are developed to combat PD itself rather than simply
alleviating symptoms.
Neuroinflammation and immunity can speed nigrostriatal degeneration in
PD. The neuroinflammatory cascade begins with aggregation of misfolded or
post-translationally modified alpha synuclein (α-syn) resulting in the occurrence
of neuronal cell death and the presence of chronically activated glia. Such
changes in the glial phenotypes can affect the central nervous system (CNS)
microenvironment by producing pro-inflammatory factors that speed nigrostriatal
degeneration.
To halt or slow disease progression, a change in the microenvironment of
the brain may be necessary. One potential mechanism to achieve this goal is
through the induction and/or enhancement of immune-modulating cells such as
regulatory T cells (Tregs). Tregs maintain immune homeostasis by suppressing
pro-inflammatory immune responses, such as those associated with
neuroinflammation and PD. Furthermore, Tregs taken from PD patients
compared to control subjects lack the capacity to suppress proliferation of other
immune cells, suggesting a dysfunctional Treg response associated with
disease. Previously, our laboratory utilized granulocyte-macrophage colonystimulating
factor (GM-CSF) to restore Treg numbers and function in animal
models and a clinical trial. This cytokine induced a neuroprotective phenotype
when assessed in animal models; however, in the clinical setting, some mild to
moderately severe adverse events were identified. Thus, it remains important to
identify different means for drug delivery or other compounds with Treg-inducing
activity and without potential untoward side effects for easy translation to human
use.
With this goal in mind, our lab evaluated the efficacy of vasoactive
intestinal peptide (VIP) analogs in the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) mouse model of PD. Our data indicate that treatment
with a stable VIP analog results in a decrease in pro-inflammatory cytokine
production, decrease in microglial reactivity, increase in neuron survival, and
increase in suppressive immune phenotypes. Taken together, these findings
support the use of VIP as a potential immunotherapy for the treatment of PD.
Recommended Citation
Olson, Katherine E., "Evaluation of Immune-Modulating Therapies For Parkinson's Disease" (2017). Theses & Dissertations. 235.
https://digitalcommons.unmc.edu/etd/235