Exposure to As-, Cd-, and Pb-Mixture Induces Aβ, Amyloidogenic APP Processing and Cognitive Impairments via Oxidative Stress-Dependent Neuroinflammation in Young Rats

Abstract

Environmental pollutants act as risk factors for Alzheimer's disease (AD), mainly affecting the aging population. We investigated early manifestations of AD-like pathology by a mixture of arsenic (As), cadmium (Cd), and lead (Pb), reported to impair neurodevelopment. We treated rats with As+Cd+Pb at their concentrations detected in groundwater of India, ie, 0.38, 0.098, and 0.22 ppm or 10 times of each, respectively, from gestation-05 to postnatal day-180. We identified dose-dependent increase in amyloid-beta (Aβ) in frontal cortex and hippocampus as early as post-weaning. The effect was strongly significant during early-adulthood, reaching levels comparable to an Aβ-infused AD-like rat model. The metals activated the proamyloidogenic pathway, mediated by increase in amyloid precursor protein (APP), and subsequent beta secretase (BACE) and presenilin (PS)-mediated APP-processing. Investigating the mechanism of Aβ-induction revealed an augmentation in oxidative stress-dependent neuroinflammation that stimulated APP expression through interleukin-responsive-APP-mRNA 5'-untranslated region. We then examined the effects of individual metals and binary mixtures in comparison with the tertiary. Among individual metals, Pb triggered maximum induction of Aβ, whereas individual As or Cd had a relatively non-significant effect on Aβ despite enhanced APP, owing to reduced induction of BACE and PS. Interestingly, when combined the metals demonstrated synergism, with a major contribution by As. The synergistic effect was significant and consistent in tertiary mixture, resulting in the augmentation of Aβ. Eventually, increase in Aβ culminated in cognitive impairments in the young rats. Together, our data demonstrate that exposure to As+Cd+Pb induces premature manifestation of AD-like pathology that is synergistic, and oxidative stress and inflammation dependent.

Sodium selenate regulates the brain ionome in a transgenic mouse model of Alzheimer’s disease

“…Almost all examined elements (12 out of 15) were considered as DCEs at one or more time points (p < 0.05, Table 1), which was also supported by repeated-measures analysis of variance (ANOVA). The majority of them appeared to be significantly enriched in the brain tissues of 3×Tg-AD mice for a relatively long period, including Fe, Zn, Cu, cadmium (Cd), mercury (Hg) and bismuth (Bi) whose levels in the brain have been reported to be elevated in AD383940414243444546. Excess Fe has been linked to the development of AD, which may combine with Aβ in the APs to accelerate neuronal Aβ production and cognitive impairment39.…”

“…Higher Hg concentrations were found in brain regions and blood of some patients with AD42. Accumulation of Cd and Bi in the brain or serum was observed to be significantly associated with AD43444546. Some other elements with increased levels in the brain of AD mice at certain time points (including arsenic (As) and lead (Pb)) are also known as neurotoxic factors.…”

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

“…Recently, Ashok [63] demonstrated that oxidative stress and inflammation induced by As, in rats exposed from 05 days of gestation and up to 180 days postnatal, lead to an enhanced APP expression that is further processed by the enzymes BACE1 and presenilin (PS), leading to an Aβ over-production. Furthermore, at 90 days post-natal exposure, animals showed a significant cognitive impairment.…”

Evaluation of interaction and combined toxicity of polyaromatic hydrocarbons (PAHs) and metals using human cell-based bioassays

“…Thus, the major limitation of the cell-based assays is the results obtained using a particular cell line can be correlated with the response of the corresponding organ in the body (e.g. (Fowler et al 2004, Agrawal et al 2015, Ashok et al 2015. Cadmium in combination with B [a]P increased the activation of the Nrf2 antioxidant response pathway and total glutathione level compared to B[a]P alone (Simon et al 2014).…”

“…The combination of As, Cd, and Pb at relevant human exposure level caused a synergistic effect on demyelination in rats (Ashok et al 2015) and produced hepatotoxic and nephrotoxic effects (Bhattacharjee et al 2016). The ATSDR released the interaction profile for Pb, As, Cd, and Cr and this profile summarises the reported data of these mixtures on various biological endpoints.…”