ABSTRACT The role of pesticide exposure in Alzheimer’s disease (AD) has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood . The goal of this proposal is to evaluate the risk for AD pathology in an animal model of early-life exposure to the pyrethroid deltamethrin (DM), a commonly use pesticide, and to assess potential therapeutic strategies to treat related memory loss in this model. Evidence indicates that DM exerts strong stimulatory effects on voltage-gated Na+ (Nav) Nav1.6 channels that are abundantly expressed in CA1 hippocampal pyramidal neurons and play a critical role in action potential initiation and propagation. During AD progression, the hippocampus is the principal brain region to display altered activity. In early phases of the disease, hyperexcitability of the hippocampal circuit caused by dysregulation of ion channels modulating the intrinsic properties of hippocampal neurons, has been ascribed as the triggering event preceding the global decline of synaptic function that characterizes late phases of the disease. Specifically, hyperactivity of Nav1.6 in the hippocampus and consequently increased firing frequency of CA1 pyramidal neurons is one of the first signs of hippocampal neurodegeneration in early-phase AD. Using a combination of MALDI imaging, immunohistochemistry, electrophysiological and behavioral assays, we will assess the influence of early-life DM exposure on Ab synaptic pathology (Aim 1), hippocampal dysfunction (Aim 2) and memory loss (Aim 3) and evaluate in vivo gene silencing targeting Nav1.6 as a therapeutic strategy for AD pathology exacerbated by pyrethroid exposure. Outcomes of this study will provide new knowledge on the gene-environment interactions underlying risk of AD.