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Growing concern has been raised over the potential adverse effects of engineered nanoparticles on human health due to their increasing use in commercial and medical applications. Silica nanoparticles (SiNPs) are one of the most widely used nanoparticles in industry and have been formulated for cellular and non-viral gene delivery in the central nerve system. However, the potential neurotoxicity of SiNPs remains largely unclear. In this study, we investigated the cellular uptake of SiNPs in human SK-N-SH and mouse neuro2a (N2a) neuroblastoma cells treated with 10.0 µg/ml of 15-nm SiNPs for 24 h by transmission electron microscopy. We found that SiNPs were mainly localized in the cytoplasm of the treated cells. The treatment of SiNPs at various concentrations impaired the morphology of SK-N-SH and N2a cells, characterized by increased number of round cells, diminishing of dendrite-like processes and decreased cell density. SiNPs significantly decreased the cell viability, induced cellular apoptosis, and elevated the levels of intracellular reactive oxygen species (ROS) in a dose-dependent manner in both cell lines. Additionally, increased deposit of intracellular β-amyloid 1-42 (Aβ1-42) and enhanced phosphorylation of tau at Ser262 and Ser396, two specific pathological hallmarks of Alzheimer's disease (AD), were observed in both cell lines with SiNPs treatment. Concomitantly, the expression of amyloid precursor protein (APP) was up-regulated, while amyloid-β-degrading enzyme neprilysin was down-regulated in SiNP-treated cells. Finally, activity-dependent phosphorylation of glycogen syntheses kinase (GSK)-3β at Ser9 (inactive form) was significantly decreased in SiNP-treated SK-N-SH cells. Taken together, these data demonstrated that exposure to SiNPs induced neurotoxicity and pathological signs of AD. The pre-Alzheimer-like pathology induced by SiNPs might result from the dys-regulated expression of APP/neprilysin and activation of GSK-3β. This is the first study with direct evidence indicating that in addition to neurotoxicity induced by SiNPs, the application of SiNPs might increase the risk of developing AD. [ABSTRACT FROM AUTHOR]

Cigarette smoking has been proposed as a major risk factor for aging-related pathological changes and Alzheimer's disease (AD). To date, little is known for how smoking can predispose our brains to dementia or cognitive impairment. This study aimed to investigate the cigarette smoke-induced pathological changes in brains. Male Sprague-Dawley (SD) rats were exposed to either sham air or 4% cigarette smoke 1 hour per day for 8 weeks in a ventilated smoking chamber to mimic the situation of chronic passive smoking. We found that the levels of oxidative stress were significantly increased in the hippocampus of the smoking group. Smoking also affected the synapse through reducing the expression of pre-synaptic proteins including synaptophysin and synapsin-1, while there were no changes in the expression of postsynaptic protein PSD95. Decreased levels of acetylated-tubulin and increased levels of phosphorylated-tau at 231, 205 and 404 epitopes were also observed in the hippocampus of the smoking rats. These results suggested that axonal transport machinery might be impaired, and the stability of cytoskeleton might be affected by smoking. Moreover, smoking affected amyloid precursor protein (APP) processing by increasing the production of sAPPβ and accumulation of β-amyloid peptide in the CA3 and dentate gyrus region. In summary, our data suggested that chronic cigarette smoking could induce synaptic changes and other neuropathological alterations. These changes might serve as evidence of early phases of neurodegeneration and may explain why smoking can predispose brains to AD and dementia. [ABSTRACT FROM AUTHOR]

Abstract  Neurofilaments (NFs) are hyperphosphorylated and accumulate in Alzheimer’s disease (AD) brains. In this study, employing the transgenic mouse model, we explored the effect of presenilin 1 (PS-1) mutation on the phosphorylation and distribution of NFs. Western blot analysis showed that there was a significant increase in the phosphorylation of NF-H and NF-M subunits with a concomitant increase in phosphorylated c-Jun N-terminal protein kinase 1/2 (JNK1/2) mitogen-activated protein kinase (MAPK) in hippocampus of PS-1 transgenic mice compared to that of wild-type littermates. Immunohistochemical analysis revealed that phosphorylated NFs accumulated throughout the hippocampal neurons of the transgenic mice. These findings suggest that PS-1 mutation may induce hyperphosphorylation and accumulation of NFs via a JNK1/2-involved mechanism. [ABSTRACT FROM AUTHOR]

INTRODUCTION This study comprehensively assessed the association between eight metabolites of urinary nicotine and cognitive impairment. METHODS This cross-sectional study was based on the data of Shenzhen Aging Related Disorder Cohort (SADC), including 51 elderly community data variables such as demographic characteristics, neuropsychological assessment and environmental factors, from July 2017 to November 2018. Participant's cognitive function was assessed by Mini-Mental State Examination (MMSE) scale and urinary nicotine metabolite [including cotinine N-β-D-glucuronide (CotGluc), rac 4-hydroxy-4-(3-pyridyl) butanoic acid dicyclohexylamine salt (HyPyBut), trans-3'-hydroxy cotinine O-β-D-glucuronide (OHCotGluc), and cotinine (Cot), etc.] concentrations were measured by high-performance liquid chromatographytandem mass spectrometry (LC-MS/MS). Generalized linear models and restricted cubic spline models were used to explore the relationships between the urinary levels of nicotine metabolite and cognitive function. RESULTS A total of 296 individuals aged >60 years were included. Individuals in the third quartile of CotGluc had a 0.786 point (95% CI: -1.244 -- -0.329) decrease or in the highest quartile of OHCotGluc had a 0.804 point (95% CI: -1.330 -- -0.278) decreased in attention and calculation compared to those in the lowest quartile (all p for trend <0.05). Compared with those in the lowest quartile, individuals in the highest quartile of CotGluc, HyPyBut, OHCotGluc and Cot, respectively, corresponded to a 1.043 point (95% CI: -2.269-0.182), 1.101 points (95% CI: -2.391-0.188), 2.318 points (95% CI: -3.615 -- -1.020), and 1.460 points (95% CI: -2.726 -- -0.194) decreased in MMSE total score (all p for trend <0.05). A nonlinear dose-response relationship between urinary levels of CotGluc, HyPyBut, OHCotGluc or Cot and cognitive function (all overall p<0.05, non-linear p<0.05). Subgroup analysis showed that urinary levels of CotGluc, OHCotGluc or Cot were significantly negatively associated with cognitive function (all p for trend <0.05) among females and non-smokers. CONCLUSIONS The findings highlight the public health implications of environmental tobacco smoke exposure, and effective interventions need to be performed for vulnerable populations. [ABSTRACT FROM AUTHOR]

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD. [ABSTRACT FROM AUTHOR]

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD. [ABSTRACT FROM AUTHOR]

Methyl tert-butyl ether (MTBE) is widely used as an oxygenating agent in gasoline to reduce harmful emissions. However, previous studies have demonstrated that MTBE is a cytotoxic substance that has harmful effects in vivo and in vitro. Although remarkable progress has been made in elucidating the mechanisms underlying the MTBE-induced reproductive toxicological effect in different cell lines, the precise mechanisms remain far from understood. The present study aimed to evaluate whether mammalian ovary cells were sensitive to MTBE exposure in vitro by assessing cell viability, lactate dehydrogenase (LDH) leakage, malondialdehyde (MDA) content and antioxidant enzyme activities. In addition, the effect of MTBE exposure on differential protein expression profiles was examined by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. MTBE exposure induced significant effects on cell viability, LDH leakage, plasma membrane damage and the activity of antioxidant enzymes. In the proteomic analysis, 24 proteins were demonstrated to be significantly affected by MTBE exposure. Functional analysis indicated that these proteins were involved in catalytic activity, binding, structural molecule activity, metabolic processes, cellular processes and localization, highlighting the fact that the cytotoxic mechanisms resulting from MTBE exposure are complex and diverse. The altered expression levels of two representative proteins, heat shock protein family A (Hsp70) members 8 and 9, were further confirmed by western blot analysis. The results revealed that MTBE exposure affects protein expression in Chinese hamster ovary cells and that oxidative stress and altered protein levels constitute the mechanisms underlying MTBE-induced cytotoxicity. These findings provided novel insights into the biochemical mechanisms involved in MTBE-induced cytotoxicity in the reproductive system. [ABSTRACT FROM AUTHOR]

Trichloroethylene (TCE) is an industrial solvent with widespread occupational exposure and also a major environmental contaminant. Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is an autoimmune disease and it has become one major hazard in China. In this study, sera from 3 healthy controls and 3 OMLDT patients at different disease stages were used for a screening study by 2D-DIGE and MALDI-TOF-MS/MS. Eight proteins including transthyretin (TTR), retinol binding protein 4 (RBP4), haptoglobin, clusterin, serum amyloid A protein (SAA), apolipoprotein A-I, apolipoprotein C-III and apolipoprotein C-II were found to be significantly altered among the healthy, acute-stage, healing-stage and healed-stage groups. Specifically, the altered expression of TTR, RBP4 and haptoglobin were further validated by Western blot analysis and ELISA. Our data not only suggested that TTR, RBP4 and haptoglobin could serve as potential serum biomarkers of OMLDT, but also indicated that measurement of TTR, RBP4 and haptoglobin or their combination could help aid in the diagnosis, monitoring the progression and therapy of the disease. [ABSTRACT FROM AUTHOR]

Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer's disease (AD), there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ), but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomericAβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD. [ABSTRACT FROM AUTHOR]