The neuroinflammatory effects of acrolein on the human microglial HMC3 cell line in relation to Alzheimer’s Disease




Black, Jeffrey

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Acrolein is a highly reactive compound that causes oxidative stress and inflammation. Excessive microglial M1 activation leads to production of pro-inflammatory factors; these factors, and subsequent neuroinflammation, have been associated with risk of developing AD pathology. The main exposure source of acrolein consists of smoking tobacco products. The daily dosage of acrolein due to cigarettes can range from 500 to 2,800 µg per day for a heavy smoker, while the dosage from e-cigarettes can range from 1.8–9 ug of acrolein. The first goal was to investigate the cytotoxicity of acrolein on the human microglial HMC3 cell line using MTT cytotoxicity & lactate dehydrogenase (LDH) assays. The second goal of this study was to determine the effect of acrolein on microglial production of neuroinflammatory cytokines and other related AD pathology proteins. These proteins were measured using immunocytochemistry (ICC) and proteomics protein multiplexing. This study provides a novel understanding of how exposure to acrolein, through use of cigarettes and e-cigarettes, can lead to a higher risk of developing AD pathology. Acrolein was proven to be cytotoxic at a much lower concentration (1-2 ug/mL) than the concentration that a heavy smoker is exposed to on a daily basis. Second, cell death and disruption, determined by LDH assay, was found to be significant at concentrations as low as 5 ug/mL. Furthermore, increased expression of CD86, measured through ICC, proved that the microglial samples being tested were M1 activated. Increased expression of RAGE, a suggested to be more potent biomarker of AD than amyloid-beta, is associated with a higher risk of developing AD. Decreased expression of P2Y12 is associated with unhealthy microglial cells. Increased IL-1B production is associated with progression of neuroinflammation, leading to development of AD through the nueroinflammatory pathway of AD pathology. Increased production of TNF-a was noted at the concentration of 2 ug/mL, but not at the concentration of 1 ug/mL. TNF-a up-regulation leads to NF-kB pathway activation. Finally, increased production of pro-inflammatory cytokines and chemokines, such as IL-6 and IL-8, measured through proteomics protein multiplexing, shows that acrolein exposure has the potential to increase the risk of developing AD.



Toxicology, Neurodegenerative disease