Arsenic Induces GSK3β-Dependent p-Tau, Neuronal Apoptosis, and Cognitive Impairment via an Interdependent Hippocampal ERα and IL-1/IL-1R1 Mechanism in Female Rats

Abstract

Arsenic is an environmental contaminant with potential neurotoxicity. We previously reported that arsenic promoted hippocampal neuronal apoptosis, inducing cognitive loss. Here, we correlated it with tau pathology. We observed that environmentally relevant arsenic exposure increased tau phosphorylation and the principal tau kinase, glycogen synthase kinase-3 beta (GSK3β), in the female rat hippocampal neurons. We detected the same in primary hippocampal neurons. Since a regulated estrogen receptor (ER) level and inflammation contributed to normal hippocampal functions, we examined their levels following arsenic exposure. Our ER screening data revealed that arsenic down-regulated hippocampal neuronal ERα. We also detected an up-regulated hippocampal interleukin-1 (IL-1) and its receptor, IL-1R1. Further, co-treating arsenic with the ERα agonist, 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), or IL-1R antagonist (IL-1Ra) resulted in reduced GSK3β and p-tau, indicating involvement of decreased ERα and increased IL-1/IL-1R1 in tau hyperphosphorylation. We then checked whether ERα and IL-1/IL-1R1 had linkage, and detected that while PPT reduced IL-1 and IL-1R1, the IL-1Ra restored ERα, suggesting their arsenic-induced interdependence. We finally correlated this pathway with apoptosis and cognition. We observed that PPT, IL-1Ra and the GSK3β inhibitor, LiCl, reduced hippocampal neuronal cleaved caspase-3 and TUNEL+ve apoptotic count, and decreased the number of errors during learning and increased the saving-memory for Y-Maze Test and retention performance for Passive avoidance test in arsenic-treated rats. Thus, our study reveals a novel mechanism of arsenic-induced GSK3β-dependent tau pathology via interdependent ERα and IL-1/IL-1R1 signaling. It also envisages the protective role of ERα agonist and IL-1 inhibitor against arsenic-induced neurotoxicity.

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…TLR3 mediated TRIF signaling was involved in the immunomodulatory effect of plant miR-168. Inflammation is a key mechanism by which arsenic leads to toxicity and human diseases. , Therefore, these plant miRNAs can be used to alleviate inflammation and inhibit the release of inflammatory factors invoked by arsenic exposure.…”

“…Arsenic is also be identified as a neurotoxin, which affects children's IQ and invokes many adverse health consequences 96 (Figure 2B). Additionally, many factors are involved in the toxic mechanisms of arsenic, including inflammation and oxidative stress, 25,27 protein degradation, 97 autophagy, 25,28−30 mitochondrial dysfunction, 98 endoplasmic reticulum (ER) stress, 99 and apoptosis. 95,100 Recently, miRNAs dysregulation was considered to be one of the important mechanisms by which arsenic leads to toxicity and human diseases, although the exact mechanism remains unclear.…”

“…Arsenic is also be identified as a neurotoxin, which affects children’s IQ and invokes many adverse health consequences (Figure B). Additionally, many factors are involved in the toxic mechanisms of arsenic, including inflammation and oxidative stress, , protein degradation, autophagy, ,− mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and apoptosis. , Recently, miRNAs dysregulation was considered to be one of the important mechanisms by which arsenic leads to toxicity and human diseases, although the exact mechanism remains unclear. ,,,, The following subsections highlight the role of miRNAs and regulatory mechanisms of miRNAs in arsenic-induced human diseases, including cancers (skin, lung, liver, kidney, bladder, and prostatic cancer), CVD, and other human diseases (DM, skin lesion, liver, lung, neurodegenerative, and kidney diseases).…”

“…More than 50 million people from West Bengal and Bangladesh were exposed to arsenic levels above 50 μg/L, which caused frequent arsenic poisoning and adverse effects on human health . A growing body of literature suggests that arsenic disrupts a series of cellular processes, including oxidative stress, cell proliferation, inflammation, and autophagy and apoptosis. ,− Arsenic exposure can lead to many adverse health effects of diabetes mellitus (DM), − skin lesions, , kidney disease, , neurological impairment, , cancers, , male reproductive injury, and cardiovascular disease (CVD) as cardiac arrhythmias, endothelial dysfunction, and ischemic heart failure. , …”