Simple SummaryEnvironmental pollutants have been suggested to be among the possible causes that play a role in the generation of Alzheimer’s disease (AD) and other neurodegenerative diseases. Included in these environmental pollutants, we find the highly used plasticizer bisphenol-A, which produces neurodegeneration and cognitive disorders similar to those induced in AD. However, the mechanisms through which this and other environmental pollutants produce these effects are unknown. In AD, as well as in other neurodegenerative diseases that produce cognitive disorders, a selective cholinergic neuronal loss is induced in the brain region of the basal forebrain, which in turn leads to the denervation of the hippocampus and cortex, producing neurodegeneration in these regions and, eventually, cognitive disorders. Our results show the alteration of some mechanisms that could mediate bisphenol-A disruption of synaptic plasticity and neurodegeneration induction in this specific type of basal forebrain neurons. These results may assist to elucidate the processes that mediate the cognition alterations produced by bisphenol-A and other environmental pollutants, which it shares mechanisms with, and could lead to the development of preventive and therapeutic tools to avoid and treat these effects in the population.AbstractThe widely used plasticizer bisphenol-A (BPA) is well-known for producing neurodegeneration and cognitive disorders, following acute and long-term exposure. Although some of the BPA actions involved in these effects have been unraveled, they are still incompletely known. Basal forebrain cholinergic neurons (BFCN) regulate memory and learning processes and their selective loss, as observed in Alzheimer’s disease and other neurodegenerative diseases, leads to cognitive decline. In order to study the BPA neurotoxic effects on BFCN and the mechanisms through which they are induced, 60-day old Wistar rats were used, and a neuroblastoma cholinergic cell line from the basal forebrain (SN56) was used as a basal forebrain cholinergic neuron model. Acute treatment of rats with BPA (40 µg/kg) induced a more pronounced basal forebrain cholinergic neuronal loss. Exposure to BPA, following 1- or 14-days, produced postsynaptic-density-protein-95 (PSD95), synaptophysin, spinophilin, and N-methyl-D-aspartate-receptor-subunit-1 (NMDAR1) synaptic proteins downregulation, an increase in glutamate content through an increase in glutaminase activity, a downregulation in the vesicular-glutamate-transporter-2 (VGLUT2) and in the WNT/β-Catenin pathway, and cell death in SN56 cells. These toxic effects observed in SN56 cells were mediated by overexpression of histone-deacetylase-2 (HDAC2). These results may help to explain the synaptic plasticity, cognitive dysfunction, and neurodegeneration induced by the plasticizer BPA, which could contribute to their prevention.