Understanding the changes in systemic immunity in the neurodegenerative disorders frontotemporal dementia and Alzeimers disease [electronic resource]

From their earliest histopathological descriptions, neurodegenerative disorders have been known to involve neuroinflammation. Yet the exact nature of the changes in inflammation, as well as the role of neuroinflammation in the pathogenesis of the disease, are not well understood. In this dissertation, I attempt to uncover the nature of the changes in the systemic immune system in neurodegeneration and the role that these changes play in disease progression. The first study presented here (Chapter 2) presents an investigation of the changes in the plasma cytokines and peripheral immune cells in Frontotemporal Dementia. Frontotemporal Dementia is the leading cause of early-onset neurodegenerative disease and is known to be caused by several mutations, including one that results in haploinsufficiency of progranulin, a gene known to attenuate inflammation. However, Frontotemporal Dementia is often sporadic, with no known genetic or environmental cause, and the underlying changes that cause this very specific, localized neurodegeneration has been unclear. In this study, we use an unbiased protein profiling platform, the antibody microarray, developed in our lab, to assay the changes in plasma protein levels in progranulin-mutation Frontotemporal Dementia and sporadic Frontotemporal Dementia. We found that there was an increase in pro-inflammatory cytokines similar to changes in cytokines observed in autoimmune disease and suggestive of changes in cellular immune phenotype. Therefore, we used a new flow cytometry technology, CyTOF by Time of Flight mass spectrometry (CyTOF), to profile immune cells in FTD patients in an unbiased manner. We found changes in CD8 T cells and Natural Killer cells similar to changes observed in autoimmune disorders. Along with colleagues at UCSF, we then conducted a retrospective study to determine if FTD patients have a higher comorbidity of autoimmune disease than the general population, and we found this to be the case. We found similar changes in inflammatory proteins and immune cells in the mouse model of Frontotemporal Dementia (GRN -/-). The next series of experiments (Chapter 3) sought to determine how the changes in the systemic protein levels in the plasma FTD patients affected the changes in the central nervous system (CNS) associated with the neurodegenerative disorders and with the changes in immune cell populations. To this end, we used two methods of introducing FTD-disease plasma to WT or GRN +/- mice: parabiosis and human plasma transfer. While we observed no changes in the strongest phenotype of the mouse model, microgliosis, in the parabiosis experiment, we observed intriguing behavior changes in GRN +/- animals treated with plasma from human FTD patients. For the next set of experiments to determine the relationship between the cytokine changes in FTD patients and the immune cell subset changes, we developed a new culture system in which we cultured whole blood with plasma-infused media, enabling us to use cells from a single donor to assay the effects of exposure of aged or FTD-patient plasma. In the final series of experiments, we sought to solidify the understanding of the changes in the systemic immune system in Alzheimer's Disease with a thorough immunophenotyping study. For four years, we collected and cryopreserved peripherial blood mononuclear cells from Alzheimer's Disease patients, resulting in a collection of over 100 samples from patients with mild to sever Alzheimer's Disease, patients with Mild Cognitive Impairment, a precursor to Alzheimer's Disease, and age-matched, cognitively healthy individuals. We developed a new CyTOF platform panel to measure the ability of cells to respond to cytokine treatment as well as the traditional immunophenotyping. We found indications that cells from Alzheimer's Disease patients are less responsive to cytokine stimuli. Collectively, this work highlights the importance of the changes in the systemic immune system in neurodegenerative disorders. It provides new insight into possible mechanisms of disease pathology and potential new avenues for future therapeutic targets.

Advisor: Wyss-Coray Anton primary advisor. Thesis advisor
Buckwalter Marion
Mignot Emmanuel
Robinson William (William Hewitt) advisor. Thesis advisor