The Role of Adaptive Immune Activation in Solvent-Induced Parkinson s Neurodegeneration
Abstract
Parkinsonism is an umbrella term that describes a spectrum of progressive, neurodegenerative movement disorders including Parkinson s disease (PD), Parkinson s disease dementia (PDD), and dementia with Lewy bodies (DLB). This spectrum is determined clinically by the onset of cognitive impairment, and pathologically by the presence of accumulated proteins; alpha-synuclein (aSyn), amyloid beta, and phosphorylated Tau. The reason for such variation between individuals as well as the mechanisms that underlie these cognitive changes remain unclear. As most parkinsonism, approximately 85%, has no genetic or inherited cause, we suspect that exogenous or environmental factors play a role in disease risk, progression, and phenotype, such as the speed and severity at which cognitive decline occurs. One environmental factor that is linked to PD risk is the organic solvent trichloroethylene (TCE) which is a degreasing compound, a chemical feedstock, and a compound used in producing refrigerants. Unfortunately, the wide application of TCE in industrial and military uses resulted in widespread occupational exposure and environmental contamination that persists due to its chlorinated structure. One of the most significant environmental contamination events with TCE occurred at U.S. Marine Corps Base Camp Lejeune, where TCE was found at extremely high levels within the water and soil for decades between the 1950s and 1980s. As a result, individuals who lived and worked at Camp Lejeune are at elevated risk for several diseases, including cancer, autoimmune disease, and PD. However, despite being a relevant PD risk factor, very little is known about the mechanisms by which TCE causes neurodegeneration and even less about cognitive impairment in diseases such as DLB. New data from our lab suggests that in addition to dopaminergic neuron loss, TCE may specifically influence cognitive dysfunction, which could partially explain the variation in Parkinsonian phenotype, provide a model system to uncover its mechanisms, and serve as a platform to test therapeutics that protect against both motor and cognitive degeneration in DLB. A well-known pathology of TCE exposure is the activation of T cells, the adaptive immune cells that monitor and respond to internal and external stimuli. Recently, new data has emerged that suggests T cell activation also plays a role in the response to aSyn accumulation, the protein that aggregates and forms Lewy bodies, and the hallmark pathology of PD, PDD, and DLB. In addition, individuals who express more activated T cells within their blood performed worse on cognition assessments, suggesting that T cell dysregulation is involved in cognitive decline. To this end, the basis of this proposal is to assess how exposure to TCE influences T cell activation and cognitive dysfunction in a model of DLB. Furthermore, we hypothesize that T cell inhibition using the U.S. Food and Drug Administration (FDA)-approved T cell inhibitor CTLA4-Ig (Abatacept, Bristol-Meyers Squibb) will be protective against TCE-induced T cell activation, neurodegeneration, and cognitive decline. To test this, we will use a rodent model of neurodegeneration that my lab established where mice are injected with preformed aSyn fibrils then exposed to 100 ppm TCE via inhalation for 1, 3, and 6 months. We observed that this model causes dopaminergic as well as hippocampal neurodegeneration, T cell infiltration within the brain, and accelerated aSyn accumulation; and we believe it more accurately models both the motor and cognitive symptoms of parkinsonism and will provide preclinical data for the use of T cell inhibition therapies in DLB. We will measure T cell activation in the brain and blood of TCE-exposed animals and identify if this correlates with worsened cognitive impairment, and measure if CTLA4-Ig therapy protects against behavioral deficits and neurodegeneration. Though TCE is a common exposure and may ultimately influence
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310788
Entities
People
- Briana De Miranda
Organizations
- United States Army
- University of Alabama at Birmingham