Specific Triazine Herbicides Induce Amyloid-β42 Production - IOS Press

"Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer’s disease (AD) hallmark. Identifying products of the ‘human chemical exposome’ (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2–10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD."



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Scientists triple known types of viruses in world's oceans

The world's oceans teem with scientific mystery, unknowns that could prove to be tools that will one day protect the planet from global warming.

An international research team now reports they've tripled the known types of viruses living in waters around the globe and have a better idea what role they play in nature. Led by Ohio State University scientists, the team includes University of Michigan biologist Melissa Duhaime.

The oceans currently soak up half of that carbon, but that comes at the cost of acidifying the oceans, which puts some ocean-dwellers, including shellfish, at risk. Understanding how microbes and viruses interact is critical to any possible management efforts, the researchers said.

Team identifies fungus in humans for first time as key factor in Crohn's disease

 "The researchers assessed the mycobiome and bacteriome of patients with Crohn's disease and their Crohn's-free first degree relatives in nine families in northern France and Belgium, and in Crohn's-free individuals from four families living in the same geographic area. Specifically, they analyzed fecal samples of 20 Crohn's and 28 Crohn's-free patients from nine families and of 21 Crohn's-free patients of four families. The researchers found strong fungal-bacterial interactions in those with Crohn's disease: two bacteria (Escherichia coli and Serratia marcescens) and one fungus (Candida tropicalis) moved in lock step. The presence of all three in the sick family members was significantly higher compared to their healthy relatives, suggesting that the bacteria and fungus interact in the intestines. Additionally, test-tube research by the Ghannoum-led team found that the three work together (with the E. coli cells fusing to the fungal cells and S. marcescens forming a bridge connecting the microbes) to produce a biofilm – a thin, slimy layer of microorganisms found in the body that adheres to, among other sites, a portion of the intestines – which can prompt inflammation that results in the symptoms of Crohn's disease."



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Chemical exposure linked to lower vitamin D levels

 Exposure to bisphenol A (BPA) and other endocrine-disrupting chemicals (EDCs) may reduce levels of vitamin D in the bloodstream, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.

Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity : Scientific Reports

Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer’s disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ1-42, Aβ2-42, and Aβ3p-42 but not the non-amyloidogenic peptides Aβ1-40 and Aβ2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβx-40. Furthermore, Aβx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

PLOS ONE: Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.




Genotoxicity Studies of Titanium Dioxide Nanoparticles (TiO2NPs) in the Brain of Mice. - PubMed - NCBI

Titanium dioxide nanoparticles (TiO2NPs) are excessively used and represent one of the top five most commonly used nanoparticles worldwide. Recently, various studies referred to their toxic potential on various organs using different treatment route. Male Swiss Webster mice were orally administrated TiO2NPs (500 mg/kg b.w.) daily for five consecutive days and then animals were sacrificed at 24 h, 7 days, or 14 days after the last treatment. The present results report that exposure to TiO2NPs produces mild to moderate changes in the cytoarchitecture of brain tissue in a time dependent manner. Moreover, Comet assay revealed the apoptotic DNA fragmentation, while PCR-SSCP pattern and direct sequencing showed point mutation of Presenilin 1 gene at exon 5, gene linked to inherited forms of the Alzheimer's disease. Therefore, from these findings, the present study concluded that TiO2NPs is genotoxic and mutagenic to brain tissue which in turn might lead to Alzheimer's disease incidence.



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What Sensory Receptors Do Outside of Sense Organs | The Scientist Magazine®

Odor, taste, and light receptors are present in many different parts of the body, and they have surprisingly diverse functions.

Cerebrospinal Fluid Biomarkers in Highly Exposed PM2.5 Urbanites: The Risk of Alzheimer’s and Parkinson’s Diseases in Young Mexico City Residents - IOS Press

Exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with Alzheimer’s disease (AD) risk, while Mn toxicity induces parkinsonism. Mexico City Metropolitan Area (MCMA) children have pre- and postnatal sustained and high exposures to PM2.5, O3, polycyclic aromatic hydrocarbons, and metals. Young MCMA residents exhibit frontal tau hyperphosphorylation and amyloid-β (Aβ)1 - 42 diffuse plaques, and aggregated and hyperphosphorylated α-synuclein in olfactory nerves and key brainstem nuclei. We measured total prion protein (TPrP), total tau (T-tau), tau phosphorylated at threonine 181 (P-Tau), Aβ1–42, α-synuclein (t-α-syn and d-α-synuclein), BDNF, insulin, leptin, and/or inflammatory mediators, in 129 normal CSF samples from MCMA and clean air controls. Aβ1–42 and BDNF concentrations were significantly lower in MCMA children versus controls (p = 0.005 and 0.02, respectively). TPrP increased with cumulative PM2.5 up to 5 μg/m3 and then decreased, regardless of cumulative value or age (R2 = 0.56). TPrP strongly correlated with T-Tau and P-Tau, while d-α-synuclein showed a significant correlation with TNFα, IL10, and IL6 in MCMA children. Total synuclein showed an increment in childhood years related to cumulated PM2.5, followed by a decrease after age 12 years (R2 = 0.47), while d-α-synuclein exhibited a tendency to increase with cumulated PM2.5 (R2 = 0.30). CSF Aβ1–42, BDNF, α-synuclein, and TPrP changes are evolving in young MCMA urbanites historically showing underperformance in cognitive processes, odor identification deficits, downregulation of frontal cellular PrP, and neuropathological AD and PD hallmarks. Neuroprotection of young MCMA residents ought to be a public health priority."




Potentially harmful chemicals widespread in household dust

Household dust exposes people to a wide range of toxic chemicals from everyday products, according to a study led by researchers at Milken Institute School of Public Health (Milken Institute SPH) at the George Washington University. The multi-institutional team conducted a first-of-a-kind meta-analysis, compiling data from dust samples collected throughout the United States to identify the top ten toxic chemicals commonly found in dust. They found that DEHP, a chemical belonging to a hazardous class called phthalates, was number one on that list. In addition, the researchers found that phthalates overall were found at the highest levels in dust followed by phenols and flame retardant chemicals."




Functional characterization of alpha-synuclein protein with antimicrobial activity.

Alpha-synuclein (α-Syn), a small (14 kDa) protein associated with Parkinson's disease, is abundant in human neural tissues. α-Syn plays an important role in maintaining a supply of synaptic vesicles in presynaptic terminals; however, the mechanism by which it performs this function are not well understood. In addition, there is a correlation between α-Syn over-expression and upregulation of an innate immune response. Given the growing body of literature surrounding antimicrobial peptides (AMPs) in the brain, and the similarities between α-Syn and a previously characterized AMP, Amyloid-β, we set out to investigate if α-Syn shares AMP-like properties. Here we demonstrate that α-Syn exhibits antibacterial activity against Escherichia coli and Staphylococcus aureus. In addition, we demonstrate a role for α-Syn in inhibiting various pathogenic fungal strains such as Aspergillus flavus, Aspergillus fumigatus and Rhizoctonia solani. We also analyzed localizations of recombinant α-Syn protein in E. coli and Candida albicans. These results suggest that in addition to α-Syn's role in neurotransmitter release, it appears to be a natural AMP.


A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism

Fecal and blood samples of infants with autism spectrum disorders (ASD) and healthy infants were analyzed to investigate the association of altered gut microbiota and ASD development. 16S rRNA gene-based sequencing found that, unlike those of healthy infants, feces of ASD infants had significantly higher and lower abundance of genera Faecalibacterium and Blautia, respectively. Moreover, DNA microarray analysis of peripheral blood mononuclear cells (PBMC) detected more highly than low expressed genes in ASD infants than in healthy infants. Gene Ontology analysis revealed that differentially expressed genes between ASD and healthy infants were involved in interferon (IFN)-γ and type-I IFN signaling pathways. Finally, strong positive correlations between expression of IFN signaling-associated genes in PBMC and fecal abundance of Faecalibacterium were found. Our results strongly suggested that altered gut microbiota in infants resulted from ASD development and was associated with systemic immunity dysregulation, especially chronic inflammation.

Esketamine produces rapid effects in treatment-resistant depression - Medical News Today

A new study in Biological Psychiatry reports that esketamine, a component of the general anesthetic ketamine, shows rapid and significant improvement in depressive symptoms in patients who do not respond to currently available therapies. The study aimed to demonstrate the efficacy and safety of esketamine in hopes to fulfill a long-awaited clinical need for therapies that can crack treatment-resistant depression.

Ketamine piqued researchers' interest when a study demonstrated that low doses of the drug have rapid antidepressant effects, alleviating symptoms within just 2 hours. This stood in stark contrast to conventional antidepressant drugs, which can take 1 to 3 months to produce an effect. In addition, ketamine appeared to work in patients who did not see improvement in symptoms with conventional antidepressant drugs, about one third of patients with major depressive disorder."




Fragrances as new contaminants in the Venice lagoon

Fragrance Materials (FMs) are omnipresent components of household and Personal Care Products (PCPs). In spite of their widespread use, little is known about their environmental occurrence. We selected 17 among the longest-lasting and most stable fragrance ingredients that are commercially available, namely: Amberketal, Ambrofix, Amyl Salicylate, Benzyl Salicylate, Bourgeonal, Dupical, Hexyl Salicylate, Isobutavan, Lemonile, Mefranal, Myraldene, Okoumal, Oranger Crystals, Pelargene, Peonile, Tridecene-2-Nitrile, Ultravanil. A new analytical method was developed to quantify FMs in water samples and it was applied to perform the first study about the distribution of these compounds in the surface waters of the city of Venice and its lagoon. Total FMs concentrations range from about 30 ng L− 1 to more than 10 μg L− 1 in polluted canals during the low tide. Sewage discharges were supposed to be the main sources of the selected FMs in the environment. Salicylates, oestrogenic and allergenic compounds, were in general the most abundant and widespread components. This study reports for the first time the detection of most of the selected FMs in surface waters and represent the first step to understand their environmental fate.

Toxic air pollution particles found in human brains

Toxic nanoparticles from air pollution have been discovered in human brains in “abundant” quantities, a newly published study reveals.

The detection of the particles, in brain tissue from 37 people, raises concerns because recent research has suggested links between these magnetite particles and Alzheimer’s disease, while air pollution has been shown to significantly increase the risk of the disease. However, the new work is still a long way from proving that the air pollution particles cause or exacerbate Alzheimer’s.

“This is a discovery finding, and now what should start is a whole new examination of this as a potentially very important environmental risk factor for Alzheimer’s disease,” said Prof Barbara Maher, at Lancaster University, who led the new research. “Now there is a reason to go on and do the epidemiology and the toxicity testing, because these particles are so prolific and people are exposed to them.”

Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis. - PubMed - NCBI

INTRODUCTION:
It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown.

OBJECTIVE:
To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients.

METHODS:
We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease.

RESULTS:
AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients.

CONCLUSION:
There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD."



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Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound -Autism Research

"Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, 2010] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc."



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Complement Biomarkers as Predictors of Disease Progression in Alzheimer’s Disease - IOS Press

There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). The growing appreciation of the importance of inflammation in early AD has focussed attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.


The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease : Nature

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.




Altered proliferation and networks in neural cells derived from idiopathic autistic individuals : Molecular Psychiatry

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.