Journal
NEUROTOXICOLOGY
Volume 86, Issue -, Pages 26-36Publisher
ELSEVIER
DOI: 10.1016/j.neuro.2021.06.008
Keywords
PFOS; ApoE; Alzheimer's disease; Amyloidogenic pathway; Tau pathology; Glycogen synthase kinase-3 beta(GSK3 beta)
Categories
Funding
- National Institute of Health STEEP grant [P42ES027706-03S1]
- Rhode Island Institutional Development Award (IDeA) Network of Biomedical Research Excellence from the National Institute of General Medical Sciences [P20GM103430]
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Alzheimer's disease is a progressive neurodegenerative disorder characterized by accumulation of beta-amyloid plaques and tau protein tangles. ApoE4 is the only known genetic risk factor for the disease. PFOS, a persistent organic pollutant, may be a potential risk factor for LOAD, influencing amyloidogenesis and tau pathology.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for approximately 60-80% of dementia cases worldwide and is characterized by an accumulation of extracellular senile plaques composed of beta-amyloid (A beta) peptide and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein. Sporadic or late-onset AD (LOAD) represents 95 % of the AD cases and its etiology does not appear to follow Mendelian laws of inheritance, thus, implicating the role of epigenetic programming and environmental factors. Apolipoprotein allele 4 (ApoE4), the only established genetic risk factor for LOAD, is suggested to accelerate the pathogenesis of AD by increasing tau hyperphosphorylation, inhibiting the clearance of amyloid-beta (A beta), and promoting A beta aggregation. Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant, with potential neurotoxic effects, that poses a major threat to the ecosystem and human health. By employing in vivo and in vitro models, the present study investigated PFOS as a potential risk factor for LOAD by assessing its impact on amyloidogenesis, tau pathology, and rodent behavior. Our behavioral analysis revealed that developmentally exposed male and female mice exhibited a strong trend of increased rearing and significantly increased distance traveled in the open field test. Biochemically, GSK3 beta and total ApoE were increased following developmental exposure, in vivo. Furthermore, in vitro, low concentrations of PFOS elevated protein levels of APP, tau, and its site-specific phosphorylation. Differentiated SH-SY5Y cells exposed to a series of PFOS concentrations, also, had elevated protein expression of GSK3 beta. These data suggest that total ApoE is inducible by environmental exposure to PFOS.
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