ABSTRACT
Perfluorooctanesulfonic acid (PFOS) is a neurotoxic widespread organic contaminant which affects several brain functions including memory, motor coordination and social activity. PFOS has the ability to traverse the placenta and the blood brain barrier (BBB) and cause weight gain in female mice. It's also known that obesity and consumption of a high fat diet have negative effects on the brain, impairs cognition and increases the risk for the development of dementia. The combination effect of developmental exposure to PFOS and the intake of a high-fat diet (HFD) has not been explored. This study investigates the effect of PFOS and /or HFD on weight gain, behavior and transcriptomic and proteomic analysis of adult brain mice. We found that female mice exposed to PFOS alone showed an increase in weight, while HFD expectedly increased body weight. The combination of HFD and PFOS exacerbated generalized behavior such as time spent in the center and rearing, while PFOS alone impacted the distance travelled. These results suggest that PFOS exposure may promote hyperactivity. The combination of PFOS and HFD alter social behavior such as rearing and withdrawal. Although HFD interfered with memory retrieval, biomarkers of dementia did not change except for total Tau and phosphorylated Tau. Tau was impacted by either or both PFOS exposure and HFD. Consistent with behavioral observations, global cerebral transcriptomic analysis showed that PFOS exposure affects calcium signaling, MAPK pathways, ion transmembrane transport, and developmental processes. The combination of HFD with PFOS enhances the effect of PFOS in the brain and affects pathways related to ER stress, axon guidance and extension, and neural migration. Proteomic analysis showed that HFD enhances the impact of PFOS on inflammatory pathways, regulation of cell migration and proliferation, and MAPK signaling pathways. Overall, these data show that PFOS combined with HFD may reprogram the genome and modulate neuromotor development and may promote symptoms linked to attention deficit-hyperactivity disorders (ADHD) and autism spectrum disorders (ASD). Future work will be needed to confirm these connections.
Subject(s)
Alkanesulfonic Acids , Dementia , Fluorocarbons , Neurodevelopmental Disorders , Pregnancy , Mice , Animals , Female , Diet, High-Fat/adverse effects , Proteomics , Weight Gain , Mice, Inbred C57BLABSTRACT
The field of Alzheimer's disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.
Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Mice, Transgenic , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , ortho-Aminobenzoates/pharmacology , ortho-Aminobenzoates/therapeutic use , tau Proteins/genetics , tau Proteins/metabolism , Amyloid beta-Peptides/metabolismABSTRACT
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 ß-amyloid (Aß) 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-ß (Aß), and promoting Aß 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, GSK3ß 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 GSK3ß. These data suggest that total ApoE is inducible by environmental exposure to PFOS.
Subject(s)
Alkanesulfonic Acids/toxicity , Alzheimer Disease/chemically induced , Alzheimer Disease/metabolism , Fluorocarbons/toxicity , Glycogen Synthase Kinase 3 beta/biosynthesis , Alzheimer Disease/pathology , Animals , Animals, Newborn , Cell Line, Tumor , Dose-Response Relationship, Drug , Female , Humans , Locomotion/drug effects , Locomotion/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Pregnancy , Risk FactorsABSTRACT
Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer's disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates.
