A Novel Mechanism by which 4-Nonylphenol Accelerates Alzheimer’s Pathogenesis and Induces both Tau-amyloid Mediated Toxicity and Neuroinflammation (P1.9-084)

Objective: This study examined groundwater contaminant 4-nonylphenol (4np)’s neurotoxicity and identified its activation of the estrogen receptor-beta (ER-beta) signaling pathway.

Background: Despite improving medical technology, current treatments for Alzheimer’s Disease (AD) can only curtail symptoms and fail to alleviate the underlying pathophysiology. The fundamental causes of AD are still unknown, but increasing quantities of scientific evidence point to environmental pollution as a contributing factor.

Design/Methods: 4np’s effects on tau-amyloid mediated apoptosis, cellular inflammation, genetic expression of inflammatory cytokines, and transgenic Caenorhabditis elegans paralysis were studied. Furthermore, to investigate if 4np activated the ER-beta pathway, estrogen receptor antagonist Tamoxifen was tested to assess the inhibition of 4np’s effects.

Results: Results demonstrated that 4np at 3μM–the average level measured in the environment, including lakes and rivers across the country–exhibited significant toxicity towards healthy neuron cells (cell viability reduced to 54%, p<0.01) and intensified inflammation (313% increase, p<0.001) in a dose and time-dependent manner. Furthermore, 4np increased transgenic C. elegans paralysis in vivo (50% of population paralyzed 5.4 hours faster than control, p<0.05), upregulated pro–inflammatory cytokine TNF–alpha expression (89% increase), adhesion factor ITGb1 expression (83% increase), and amyloid mediator BACE–1 expression (96% increase), while downregulating anti–inflammatory cytokine IL–10 expression (51% decrease). Tamoxifen, however, was able to confer protection against 4np neurotoxicity (28% increase in cell survival, p<0.001), attenuate 4np-induced inflammation (81% reduction, p<0.001), and suppress 4np’s upregulation of inflammatory cytokines. Because the concentration of 4np tested in this study mimicked the levels found in the environment (0.3μM), the results demonstrated an urgent need for restrictive measures on 4np production. Tamoxifen’s ability to ameliorate 4np toxicity also suggested that the contaminant activated the ER-beta signaling pathway.

Conclusions: Ultimately, this project accomplished two novel endeavors: determine 4np’s effect on AD pathogenesis and identify the pathways involved, subsequently proposing a possible solution.

Disclosure: Kevin Zhong has nothing to disclose.