Project Summary Alzheimer's disease (AD) is a progressive brain disorder associated with continuous decline in thinking that leads to loss of behavioral, social, and cognitive skills. Memory loss is the key symptom of AD. It is a major public health concern and a tremendous economic and societal challenge. Minority communities, such as Hispanic and Black, are disproportionately affected by this disease. AD is a neurodegenerative disease, and its pathology is characterized by extensive neuronal loss and the deposition of two abnormal protein structures, amyloid plaques (composed of amyloid -protein) and neurofibrillary tangles (composed of the microtubule-associated protein, Tau) in the affected brain regions. Aging is the most consistent risk factor in developing AD and recent evidence suggests that environmental factors play a significant role in this process. 4- Nonylphenol (4-NP) is an endocrine-disrupting compound (EDC) and an environmental pollutant that has recently been implicated as a risk factor for AD and AD-related dementia. 4-NP has been of environmental concern for decades due of its toxicity, estrogenic properties, and widespread contamination in the environment including water, air, and soil. Research from our laboratory demonstrates that 4-NP disrupts microtubules (MT) and alters the localization and expression of Tau, the MT-associated protein. The Tau protein and its phosphorylation status has been shown to be linked to the initiation and progression of AD and AD-related dementia. Earlier studies have exhibited that 4-NP exposure produces learning and memory impairment in adult rats and causes behavioral and cognitive deficits in offspring when exposed prenatally. Our preliminary studies indicate that 4-NP causes a substantial neuronal loss in zebrafish embryos. Altogether, these results point towards the adverse effects of 4-NP on neuronal development, neurodegeneration, and learning/memory. Therefore, our hypothesis is that exposure of 4-NP can induce AD-like pathology and behavior by disrupting the cytoskeleton and inducing tau hyperphorylation and protein aggregation. Both cell cultures and a zebrafish model will be used to conduct the study. We will test our hypothesis by addressing the following two specific aims. In Aim-1, we will determine the mechanism of 4-NP-induced cytoskeletal disruption and Tau hyperphosphorylation in a cell culture model. The goal of Aim-2 is to utilize the zebrafish model to study the effects of 4-NP on learning and memory deficits. It is anticipated that the proposed study will delineate the mechanism by which 4-NP induces AD and related dementia, which affect the Hispanic population in U.S./Mexico border communities disproportionately.