Our current project is focused on understanding the initial neuroinflammatory changes that occur in the CNS as the result of exposure to disease-associated environmental toxicants to determine how age-related neurodegenerative disorders of the elderly are initiated and progress. In the ongoing study, we have identified the NLRP3 inflammasome as a key mediator of neuroinflammation resulting from pesticide exposure in a Parkinson?s disease (PD) model and characterized NLRP3 expression in mesencephalic tissues obtained from PD patients. Our discovery of a role for NLRP3 in PD is consistent with recent reports of a role for NLRP3 in Alzheimer?s disease (AD). We do not yet know whether NLRP3 and toxicant exposure are related in the pathogenesis of AD and therefore propose to leverage our laboratory?s expertise to determine if NLRP3 also has a role in pesticide-induced neuroinflammation associated with the development of AD symptomology. To this end, we will expose wild-type and Nlrp3-/- mice to chlorpyrifos (CPF), a widely-used pesticide linked to AD by multiple recent reports. We will expose mice either in utero or throughout adulthood and conduct longitudinal behavioral analysis in aging mice followed by post-mortem studies of neurodegeneration and amyloid pathology in CNS tissues. The integration of these experiments into our current project will broaden our platform for understanding the importance of inflammasomes in the response to environmental toxicants known to increase the risk of developing age-related neurologic disorders and allow us to expand our established research program to include the rigorous analysis of AD-related pathologies.
Alzheimer?s disease is age-related but recent studies indicate that environmental pollutants may also impact the incidence and progression of the disease. Our ongoing project has identified cellular inflammasomes as potential mediators of brain inflammation in mice exposed to pesticides. In this study, we will determine whether the inflammasome gene Nlrp3 is required for brain inflammation and the development of Alzheimer?s symptoms in aging mice exposed chronically to a commonly used pesticide.
| von Herrmann, Katharine M; Salas, Lucas A; Martinez, Eileen M et al. (2018) NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson's disease. NPJ Parkinsons Dis 4:24 |
| Martinez, Eileen M; Young, Alison L; Patankar, Yash R et al. (2017) Editor's Highlight: Nlrp3 Is Required for Inflammatory Changes and Nigral Cell Loss Resulting From Chronic Intragastric Rotenone Exposure in Mice. Toxicol Sci 159:64-75 |
