Abstract
A number of experimental investigations utilizing different murine species have previously reported: (i) that standard mouse-diets supplemented with physiologically realistic amounts of neurotoxic metal salts substantially induce pro-inflammatory signaling in a number of murine tissues; (ii) that these diet-stimulated changes may contribute to a systemic inflammation (SI), a potential precursor to neurodegenerative events in both the central and the peripheral nervous system (CNS, PNS); and (iii) that these events may ultimately contribute to a chronic and progressive inflammatory neurodegeneration, such as that which is observed in Alzheimer’s disease (AD) brain. In these experiments we assayed for markers of SI in the blood serum of C57BL/6J mice after 0, 1, 3 and 5 months of exposure to a standard mouse diet that included aluminum-sulfate in the food and drinking water, compared to age-matched controls receiving magnesium-sulfate or no additions. The data indicate that the SI markers that include the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the acute phase reactive protein C-reactive protein (CRP) production and a triad of pro-inflammatory microRNAs (miRNA-9, miRNA-125b and miRNA-146a) all increase in the serum after aluminum-sulfate exposure. For the first time these results suggest that ad libitum exposure to aluminum-sulfate at physiologically realistic concentrations, as would be found in the human diet over the long term, may predispose to SI and the potential development of chronic, progressive, inflammatory neurodegeneration with downstream pathogenic consequences.
Highlights
Systemic inflammation (SI) as a precursor to neurodegenerative diseaseSystemic inflammation (SI) (i) represents a chronic and global-state of inflammation in human physiology that affects multiple tissues and organ systems; (ii) is a consequence of the release of pro-inflammatory cytokines from endothelial, mast and other immune-related cells into the bloodstream; and (iii) involves the activation and re-activation of the innateimmune system
C-reactive protein (CRP), IL-6 and TNFα each showed steady increases over the 0–5 month time period indicating the proliferation of pro-inflammatory markers in blood serum and the potential propagation of a systemic inflammation (SI); at the 1 month time-point CRP, IL-6 and TNFα had increased to ~3.1, 2.1 and 2.7-fold, respectively, over age matched controls; at the 5 month time-point CRP, IL-6 and TNFα were found to increase ~13.1, 8.1 and 9.1-fold over age-matched controls; all 3 inflammatory biomarkers showed very significant increases in the blood serum after 5 months (Figures 1A and 1B)
For ease of comparison all CRP levels are shown relative to the CRP levels at ‘0’ time which was ~2.0 ug/ml (Figure 1A); for ease of comparison all IL-6 and TNFα levels are shown relative to the IL-6 and TNFα levels at ‘0’ time which was ~5 pg/ml (Figure 1B)
Summary
Systemic inflammation (SI) as a precursor to neurodegenerative diseaseSystemic inflammation (SI) (i) represents a chronic and global-state of inflammation in human physiology that affects multiple tissues and organ systems; (ii) is a consequence of the release of pro-inflammatory cytokines from endothelial, mast and other immune-related cells into the bloodstream; and (iii) involves the activation and re-activation of the innateimmune system. In SI, blood-borne pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), acute phase reactive proteins such as C-reactive protein (CRP) and related inflammatory mediators such as novel bioactive docosanoids and fatty acids carry inflammatory signals throughout the systemic vasculature that may cross defective physiological barriers between the PNS and CNS [1,2,3,4,5,6]. These actions appear to further recruit immune cells in the brain and exacerbate neuro-inflammation. Controversial, aluminum intake has been tentatively linked (i) to both SI and neuroinflammatory signaling up-regulation in AD [4,7,13,14]; (ii) to increased oxidative stress, oxidized fatty acids, isoprostane generation and pro-inflammatory signaling in murine transgenic models of neurodegenerative disease (Tg2576) [15]; (iii) to the induction of proinflammatory and pro-apoptotic gene expression patterns in human brain cells in primary culture [11]; (iv) to increased production of pro-inflammatory cytokines such as IL-6 in the immune system by aluminum oxide nanoparticles [16]; (v) to the abundance of the SI biomarker C-reactive protein (CRP) in human brain micro vessel endothelial cells that line the cerebral vasculature [6,17]; and most recently (vi) to increased inflammation in the peripheral nervous system in rats supplemented with aluminum in their diet [18]
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