Involvement of Insulin Signaling Disturbances in Bisphenol A-Induced Alzheimer’s Disease-like Neurotoxicity

Abstract

Bisphenol A (BPA), a member of the environmental endocrine disruptors (EDCs), has recently received increased attention because of its effects on brain insulin resistance. Available data have indicated that brain insulin resistance may contribute to neurodegenerative diseases. However, the associated mechanisms that underlie BPA-induced brain-related outcomes remain largely unknown. In the present study, we identified significant insulin signaling disturbances in the SH-SY5Y cell line that were mediated by BPA, including the inhibition of physiological p-IR Tyr1355 tyrosine, p-IRS1 tyrosine 896, p-AKT serine 473 and p-GSK3α/β serine 21/9 phosphorylation, as well as the enhancement of IRS1 Ser307 phosphorylation; these effects were clearly attenuated by insulin and rosiglitazone. Intriguingly, Alzheimer’s disease (AD)-associated pathological proteins, such as BACE-1, APP, β-CTF, α-CTF, Aβ 1–42 and phosphorylated tau proteins (S199, S396, T205, S214 and S404), were substantially increased after BPA exposure, and these effects were abrogated by insulin and rosiglitazone treatment; these findings underscore the specific roles of insulin signaling in BPA-mediated AD-like neurotoxicity. Thus, an understanding of the regulation of insulin signaling may provide novel insights into potential therapeutic targets for BPA-mediated AD-like neurotoxicity.

Neurochemical characterization of the enteric neurons within the porcine jejunum in physiological conditions and under the influence of bisphenol A (BPA)

“…Previous studies showed that BPA may affect the nervous system, not only by estrogen receptors, which are widespread in the central and peripheral (also in the ENS) nervous system, but also through several types of other types of receptors. These include (among others) insulin receptor, glucocorticoid receptor, and gamma‐aminobutyric acid receptor . The administration of BPA results in disorders in the development and growth of projections of neuronal cells and changes in synaptogenesis .…”

“…Moreover, even short exposure to BPA may result in disorders in higher neural activity, including learning, cognition, and memorizing, which may occur a long time after intoxication . Moreover, previous studies have suggested that there is a relationship between exposure to BPA and the risk of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases . In turn, in the reproductive system, exposure to BPA may result in the changes within the uterus, including the inhibition of uterine epidermal apoptosis and an increase in the thickness of the uterine mucosal layer .…”

“…6,10 Moreover, previous studies have suggested that there is a relationship between exposure to BPA and the risk of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. 11,12 In turn, in the reproductive system, exposure to BPA may result in the changes within the uterus, including the inhibition of uterine epidermal apoptosis and an increase in the thickness of the uterine mucosal layer. 13 Moreover, it is known that exposure to BPA results in disturbances in estrogen metabolism, disorders in the estrus cycle, pregnancy, and embryo implantation.…”

The Neurochemical Characterization of Parasympathetic Nerve Fibers in the Porcine Uterine Wall Under Physiological Conditions and After Exposure to Bisphenol A (BPA)

“…The changes mentioned above lead to disturbances in higher neuronal functions, such as behavior, memory, and/or learning (Johnson et al 2016 ). Some neuronal symptoms may appear only after many months of exposure to BPA (Hutter et al 2016 ), and in the light of the previous studies, the participation of BPA in the pathogenesis of neurodegenerative diseases, including Alzheimer’s or Parkinson’s diseases, cannot be excluded (Landolfi et al 2017 ; Wang et al 2017 ).…”

Methamphetamine exposure upregulates the amyloid precursor protein and hyperphosphorylated tau expression: The roles of insulin signaling in SH-SY5Y cell line

“…As the precursor protein of the Aβ, APP plays critical roles in the development of AD (Leinonen et al, 2010;Wang et al, 2017), we then sought to examine whether METH exposure increases APP expression. To investigate the specific effects of METH on APP expression, the SH-SY5Y cells were incubated with varied concentration (0, 100, 300, 1000 μM) of METH for 12 hr, then the protein level of APP were detected.…”