Nlrp3 in the development of Alzheimer's pathology in aging mice exposed to chlorpyrifos

Dartmouth College, Hanover NH

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Abstract

Abstract 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.