Publisher: BMC (Biomed Central)   (Total: 310 journals)

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Showing 201 - 310 of 310 Journals sorted by number of followers
Applied Cancer Research     Open Access   (Followers: 3)
J. of Clinical Movement Disorders     Open Access   (Followers: 3)
Fertility Research and Practice     Open Access   (Followers: 2)
Intl. J. of Retina and Vitreous     Open Access   (Followers: 2)
Clinical and Translational Allergy     Open Access   (Followers: 2, SJR: 1.425, CiteScore: 4)
Biology of Sex Differences     Open Access   (Followers: 2, SJR: 1.902, CiteScore: 4)
Fisheries and Aquatic Sciences     Open Access   (Followers: 2, SJR: 0.199, CiteScore: 0)
J. of Angiogenesis Research     Open Access   (Followers: 2)
Public Health Reviews     Open Access   (Followers: 2, SJR: 0.454, CiteScore: 1)
BMJ Evidence-Based Medicine     Hybrid Journal   (Followers: 2)
BMC Rheumatology     Open Access   (Followers: 2)
Contraception and Reproductive Medicine     Open Access   (Followers: 2)
J. of Biomedical Semantics     Open Access   (Followers: 2, SJR: 0.952, CiteScore: 2)
Inflammation and Regeneration     Open Access   (Followers: 2)
Cancers of the Head & Neck     Open Access   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 2, SJR: 0.57, CiteScore: 2)
J. of Inflammation     Open Access   (Followers: 2, SJR: 1.101, CiteScore: 3)
Cell Communication and Signaling     Open Access   (Followers: 2, SJR: 2.211, CiteScore: 4)
BMC Pharmacology     Open Access   (Followers: 2)
Cancer Nanotechnology     Open Access   (Followers: 2, SJR: 1.168, CiteScore: 4)
J. of Neuroinflammation     Open Access   (Followers: 2, SJR: 2.336, CiteScore: 5)
Fluids and Barriers of the CNS     Open Access   (Followers: 2, SJR: 2.054, CiteScore: 5)
Reproductive Health     Open Access   (Followers: 2, SJR: 1.228, CiteScore: 2)
Italian J. of Pediatrics     Open Access   (Followers: 2, SJR: 0.685, CiteScore: 2)
Molecular Neurodegeneration     Open Access   (Followers: 2, SJR: 3.418, CiteScore: 7)
Plant Methods     Open Access   (Followers: 2, SJR: 1.885, CiteScore: 4)
Neural Development     Open Access   (Followers: 2, SJR: 1.821, CiteScore: 2)
Particle and Fibre Toxicology     Open Access   (Followers: 2, SJR: 2.253, CiteScore: 8)
Canine Genetics and Epidemiology     Open Access   (Followers: 1)
Acta Neuropathologica Communications     Open Access   (Followers: 1, SJR: 2.683, CiteScore: 5)
Pilot and Feasibility Studies     Open Access   (Followers: 1)
Eye and Vision     Open Access   (Followers: 1)
Cerebellum & Ataxias     Open Access   (Followers: 1)
Longevity & Healthspan     Open Access   (Followers: 1)
Translational Neurodegeneration     Open Access   (Followers: 1, SJR: 1.901, CiteScore: 5)
Asthma Research and Practice     Open Access   (Followers: 1)
J. of Environmental Health Science & Engineering     Open Access   (Followers: 1, SJR: 0.802, CiteScore: 3)
Animal Biotelemetry     Open Access   (Followers: 1, SJR: 1.067, CiteScore: 2)
BMC Zoology     Open Access   (Followers: 1)
Bioelectronic Medicine     Open Access   (Followers: 1)
Advances in Rheumatology     Open Access   (Followers: 1)
Cancer Convergence     Open Access   (Followers: 1)
European J. of Medical Research     Open Access   (Followers: 1, SJR: 0.55, CiteScore: 1)
Scoliosis and Spinal Disorders     Open Access   (Followers: 1, SJR: 0.843, CiteScore: 2)
Women's Midlife Health     Open Access   (Followers: 1)
Genes and Environment     Open Access   (Followers: 1, SJR: 0.516, CiteScore: 1)
Gynecologic Oncology Research and Practice     Open Access   (Followers: 1)
Tropical Diseases, Travel Medicine and Vaccines     Open Access   (Followers: 1)
COPD Research and Practice     Open Access   (Followers: 1, SJR: 0.755, CiteScore: 2)
Infectious Diseases of Poverty     Open Access   (Followers: 1, SJR: 1.212, CiteScore: 3)
Orphanet J. of Rare Diseases     Open Access   (Followers: 1, SJR: 1.413, CiteScore: 3)
Philosophy, Ethics, and Humanities in Medicine     Open Access   (Followers: 1, SJR: 0.285, CiteScore: 1)
Proteome Science     Open Access   (Followers: 1, SJR: 0.792, CiteScore: 2)
Skeletal Muscle     Open Access   (Followers: 1, SJR: 2.32, CiteScore: 4)
J. of Venomous Animals and Toxins including Tropical Diseases     Open Access   (Followers: 1, SJR: 0.573, CiteScore: 2)
J. of Medical Case Reports     Open Access   (Followers: 1, SJR: 0.331, CiteScore: 1)
Acta Veterinaria Scandinavica     Open Access   (Followers: 1, SJR: 0.655, CiteScore: 1)
BMC Ear, Nose and Throat Disorders     Open Access   (Followers: 1, SJR: 0.653, CiteScore: 2)
Cell Division     Open Access   (Followers: 1, SJR: 2.445, CiteScore: 4)
Head & Face Medicine     Open Access   (Followers: 1, SJR: 0.62, CiteScore: 2)
Theoretical Biology and Medical Modelling     Open Access   (Followers: 1, SJR: 0.783, CiteScore: 2)
Respiratory Research     Open Access   (Followers: 1, SJR: 1.644, CiteScore: 4)
World J. of Surgical Oncology     Open Access   (Followers: 1, SJR: 0.688, CiteScore: 2)
Biological Research     Open Access   (Followers: 1, SJR: 0.654, CiteScore: 2)
Investigative Genetics     Open Access   (Followers: 1, SJR: 1.809, CiteScore: 3)
Hereditas     Open Access   (Followers: 1, SJR: 0.278, CiteScore: 1)
Basic and Clinical Andrology     Open Access   (Followers: 1, SJR: 0.564, CiteScore: 2)
World Allergy Organization J.     Open Access   (Followers: 1, SJR: 1.936, CiteScore: 6)
Thyroid Research     Open Access   (Followers: 1, SJR: 0.329, CiteScore: 1)
J. of Cardiovascular Magnetic Resonance     Open Access   (Followers: 1, SJR: 2.292, CiteScore: 5)
BMC Proceedings     Full-text available via subscription   (Followers: 1, SJR: 0.302, CiteScore: 1)
Molecular Cytogenetics     Open Access   (Followers: 1, SJR: 0.623, CiteScore: 1)
Measurement Instruments for the Social Sciences     Open Access  
BMC Energy     Open Access  
Sustainable Earth     Open Access  
BMC Biomedical Engineering     Open Access  
BMC Chemical Engineering     Open Access  
ExRNA     Open Access  
J. of Cotton Research     Open Access  
Biomedical Dermatology     Open Access  
Cancer Communications     Open Access  
Diagnostic and Prognostic Research     Open Access  
Porcine Health Management     Open Access  
Neurovascular Imaging     Open Access  
NeuroMetals     Open Access  
Chinese Neurosurgical J.     Open Access  
Cardio-Oncology     Open Access  
Neuropsychiatric Electrophysiology     Open Access  
Research Involvement and Engagement     Open Access  
J. of Biological Research - Thessaloniki     Open Access   (SJR: 0.32, CiteScore: 2)
J. of Therapeutic Ultrasound     Open Access   (SJR: 0.906, CiteScore: 3)
Cilia     Open Access   (SJR: 0.732, CiteScore: 1)
Israel J. of Health Policy Research     Open Access   (SJR: 0.488, CiteScore: 1)
Vascular Cell     Open Access   (SJR: 1.349, CiteScore: 4)
Clinical Sarcoma Research     Open Access  
Standards in Genomic Sciences     Open Access   (SJR: 0.768, CiteScore: 2)
Mobile DNA     Open Access   (SJR: 3.783, CiteScore: 5)
J. of Neurodevelopmental Disorders     Open Access   (SJR: 1.71, CiteScore: 4)
Biological Procedures Online     Open Access   (SJR: 1.352, CiteScore: 4)
Hereditary Cancer in Clinical Practice     Open Access   (SJR: 0.848, CiteScore: 2)
PMC Biophysics     Open Access  
Fibrogenesis & Tissue Repair     Open Access   (SJR: 1.531, CiteScore: 4)
J. of Ovarian Research     Open Access   (SJR: 1.008, CiteScore: 3)
Source Code for Biology and Medicine     Open Access   (SJR: 0.784, CiteScore: 2)
Retrovirology     Open Access   (SJR: 1.855, CiteScore: 3)
Lipids in Health and Disease     Open Access   (SJR: 0.915, CiteScore: 2)
J. of Negative Results in BioMedicine     Open Access   (SJR: 0.483, CiteScore: 1)
J. of Ethnobiology and Ethnomedicine     Open Access   (SJR: 0.693, CiteScore: 3)
Infectious Agents and Cancer     Open Access   (SJR: 0.855, CiteScore: 2)
Harm Reduction J.     Open Access   (SJR: 1.445, CiteScore: 3)

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Acta Neuropathologica Communications
Journal Prestige (SJR): 2.683
Citation Impact (citeScore): 5
Number of Followers: 1  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2051-5960
Published by BMC (Biomed Central) Homepage  [310 journals]
  • Clinical and neuropathological phenotype associated with the novel V189I
           mutation in the prion protein gene

    • Abstract: Abstract Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85–90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10–15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases. We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD. Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.
      PubDate: 2019-01-03
       
  • A pathogenic tau fragment compromises microtubules, disrupts insulin
           signaling and induces the unfolded protein response

    • Abstract: Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention.
      PubDate: 2019-01-03
       
  • Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s
           disease retinas

    • Abstract: Abstract In-vivo labeling of retinal amyloid-beta(Aβ) and tau has potential as non-invasive biomarker for Alzheimer’s disease (AD). However, literature on the presence of Aβ and phosphorylated tau (pTau) in AD retinas is inconclusive. We therefore assessed the presence of Aβ and pTau in post-mortem retinas in 6 AD and 6 control cases who donated brains and eyes to the Netherlands Brain Bank. Neuropathological diagnosis of AD was made according to NIA-AA criteria. Formalin fixed retinas were dissected in quadrants and cross-sections of medial and superior retinas were made. Immuno-histochemical stainings were performed for Aβ, amyloid precursor protein (APP) and pTau. To assess translation to an in-vivo set up using curcumin as labelling fluorophore, co-stainings with curcumin were performed. No typical Aβ-plaques and neurofibrillary tangles, like in the cerebral cortex, were observed in AD retinas. A diffuse immunoreactive signal for pTau was increased in the inner and outer plexiform layers of the retina in AD cases compared to control cases with absence of cerebral amyloid pathology. Immunostaining with anti-Aβ and anti-APP antibodies yielded signal in ganglion cells, amacrine cells, horizontal cells and Müller cells in both control and AD cases. We observed small extracellular deposits positive for anti-Aβ antibodies 12F4 and 6E10 and negative for 4G8 and curcumin. A subset of these deposits could be characterized as corpora amylacea. In conclusion we found that retinal manifestations of AD pathology appear to be different compared to cerebral AD pathology. Using a qualitative cross-sectional approach, we did not find Aβ/APP related differences in the retina between AD and control subjects. In contrast, tau related changes were found to be present in cases with cerebral AD pathology, suggesting retinal tau as a potential biomarker for AD.
      PubDate: 2018-12-28
       
  • A functional genomics approach to identify pathways of drug resistance in
           medulloblastoma

    • PubDate: 2018-12-27
       
  • Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel
           lysosomal storage disease – a new type of neuronal ceroid lipofuscinosis
           (CLN15)'

    • Abstract: Abstract Homozygous mutation of TBC1 domain-containing kinase (TBCK) is the cause of a very recently defined severe childhood disorder, which is characterized by severe hypotonia, global developmental delay, intellectual disability, epilepsy, characteristic facies and premature death. The link between TBCK loss of function and symptoms in patients with TBCK deficiency disorder (TBCK-DD) remains elusive. Here we demonstrate for the first time the histopathological characteristics of TBCK deficiency consisting of 1) a widespread and massive accumulation of lipofuscin storage material in neurons of the central nervous system without notable neuronal degeneration, 2) storage deposits in few astrocytes, 3) carbohydrate-rich deposits in brain, spleen and liver and 4) vacuolated lymphocytes. Biochemical examinations ruled out more than 20 known lysosomal storage diseases. These investigations strikingly uncover TBCK-DD as a novel type of lysosomal storage disease which is characterized by different storage products rather than one specific type of accumulated material. Due to the clear predominance of intraneuronal lipofuscin storage material and the characteristic clinical presentation we propose to classify this disease as a new subtype of neuronal ceroid lipofuscinosis (CLN15). Our results and previous reports suggest an autophagosomal-lysosomal dysfunction caused by enhanced mTORC1-mediated autophagosome formation and reduced Rab-mediated autophagosome-lysosome fusion, thus disclosing potential novel targets for therapeutic approaches in TBCK-DD.
      PubDate: 2018-12-27
       
  • GJA1 (connexin43) is a key regulator of Alzheimer’s disease
           pathogenesis

    • Abstract: Abstract GJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated with Alzheimer’s disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic and proteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was strongly associated with AD amyloid and tau pathologies and cognitive functions. RNA sequencing analysis of Gja1−/− astrocytes validated that Gja1 regulated the subnetwork identified in AD, and many genes involved in Aβ metabolism. Astrocytes lacking Gja1 showed reduced Apoe protein levels as well as impaired Aβ phagocytosis. Consistent with this, wildtype neurons co-cultured with Gja1−/− astrocytes contained higher levels of Aβ species than those with wildtype astrocytes. Moreover, Gja1−/− astrocytes was more neuroprotective under Aβ stress. Our results underscore the importance of GJA1 in AD pathogenesis and its potential for further investigation as a promising pharmacological target in AD.
      PubDate: 2018-12-21
       
  • Long term follow-up and further molecular and histopathological studies in
           the LGMD1F sporadic TNPO3 -mutated patient

    • PubDate: 2018-12-19
       
  • Dichotomous scoring of TDP-43 proteinopathy from specific brain regions in
           27 academic research centers: associations with Alzheimer’s disease and
           cerebrovascular disease pathologies

    • Abstract: Abstract TAR-DNA binding protein 43 (TDP-43) proteinopathy is a common brain pathology in elderly persons, but much remains to be learned about this high-morbidity condition. Published stage-based systems for operationalizing disease severity rely on the involvement (presence/absence) of pathology in specific anatomic regions. To examine the comorbidities associated with TDP-43 pathology in aged individuals, we studied data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set. Data were analyzed from 929 included subjects with available TDP-43 pathology information, sourced from 27 different American Alzheimer’s Disease Centers (ADCs). Cases with relatively unusual diseases including autopsy-proven frontotemporal lobar degeneration (FTLD-TDP or FTLD-tau) were excluded from the study. Our data provide new information about pathologic features that are and are not associated with TDP-43 pathologies in different brain areas—spinal cord, amygdala, hippocampus, entorhinal cortex/inferior temporal cortex, and frontal neocortex. Different research centers used cite-specific methods including different TDP-43 antibodies. TDP-43 pathology in at least one brain region was common (31.4%) but the pathology was rarely observed in spinal cord (1.8%) and also unusual in frontal cortex (5.3%). As expected, TDP-43 pathology was positively associated with comorbid hippocampal sclerosis pathology and with severe AD pathology. TDP-43 pathology was also associated with comorbid moderate-to-severe brain arteriolosclerosis. The association between TDP-43 pathology and brain arteriolosclerosis appears relatively specific since there was no detected association between TDP-43 pathology and microinfarcts, lacunar infarcts, large infarcts, cerebral amyloid angiopathy (CAA), or circle of Willis atherosclerosis. Together, these observations provide support for the hypothesis that many aged brains are affected by a TDP-43 proteinopathy that is more likely to be seen in brains with AD pathology, arteriolosclerosis pathology, or both.
      PubDate: 2018-12-19
       
  • Deficit of corpus callosum axons, reduced axon diameter and decreased area
           are markers of abnormal development of interhemispheric connections in
           autistic subjects

    • Abstract: Introduction In autism spectrum disorder, lack of coherence and of complex information processing, and narrowly focused interests and repetitive behaviors are considered a sign of long-range underconnectivity and short-range overconnectivity. The goal of this morphometric study of five anatomically and functionally different segments of the corpus callosum (CC) was to establish patterns of differences between long-range interhemispheric connections in nine neurotypical and nine autistic subjects. Results Electron microscopy revealed a significant reduction in average axon diameter and axon cross-sectional area in autistic subjects, and reduction in CC segment–specific diversification of connections of functionally different cortical regions. The study shows an increase in the percentage of small diameter axons (< 0.651 μm) and a decrease in the percentage of axons with large diameter (> 1.051 μm). The total number of small-diameter axons is reduced in segment I and III by 43% on average. The number of medium- and large-diameter axons is reduced in all five CC segments by an average of 49 and 72%, respectively. Conclusions The detected pattern of pathology suggests a failure of mechanisms controlling guidance of axons during development leading to axonal deficit, and failure of mechanisms controlling axon structure. A reduction in axon diameter may affect the velocity and volume of signal transmission, and distort functional specialization of CC segments. Significant deficits in axon number and reduction in axon size in all five CC segments appear to be substantial components of brain connectome integrity distortion which may contribute to the autism phenotype.
      PubDate: 2018-12-19
       
  • Analysis of spinal and muscle pathology in transgenic mice overexpressing
           wild-type and ALS-linked mutant MATR3

    • Abstract: Abstract Mutations in MATR3 have been associated with amyotrophic lateral sclerosis (ALS) as well as a form of distal myopathy termed vocal cord pharyngeal distal myopathy (VCPDM). To begin to understand how mutations in MATR3 may cause disease, here we provide initial characterization of transgenic (Tg) mice expressing human wild-type (WT) MATR3 (MATR3WT) and ALS-mutant F115C MATR3 (MATR3F115C) proteins under the control of the mouse prion promoter (MoPrP). For each construct, we established multiple independent lines of mice that stably transmitted the transgene. Unexpectedly, for all stably-transmitting lines examined, MATR3 transgenic mRNA expression was more robust in muscle, with minimal expression in spinal cord. The levels of transgenic mRNA in muscle did not differ between mice from our lead MATR3F115C line and lead MATR3WT line, but mice from the lead MATR3F115C line had significantly higher levels of MATR3 protein in muscle over the lead MATR3WT line. Mice from the three independent, established lines of MATR3F115C mice developed weakness in both fore- and hind-limbs as early as < 1 months of age; whereas, MATR3WT mice aged to > 20 months were not overtly distinguishable from non-transgenic (NT) littermates based on basic motor phenotype. Muscle of both MATR3WT and MATR3F115C mice showed vacuoles by 2 months of age which worsened by ~ 10 months, but vacuolation was noticeably more severe in MATR3F115C mice. Overall, our results indicate that increasing the levels of MATR3 in muscle can cause pathologic changes associated with myopathy, with MATR3F115C expression causing overt muscle atrophy and a profound motor phenotype. The findings suggest that analysis of muscle pathology in individuals harboring ALS-linked MATR3 mutations should be routinely considered.
      PubDate: 2018-12-19
       
  • Co-occurrence of chronic traumatic encephalopathy and prion disease

    • Abstract: Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrPD) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrPD type were used as controls. The histopathology phenotype and PrPD properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrPD conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10− 6). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.
      PubDate: 2018-12-18
       
  • Mitochondrial transfer from mesenchymal stem cells to neural stem cells
           protects against the neurotoxic effects of cisplatin

    • Abstract: Abstract Mesenchymal stem cells (MSCs) transfer healthy mitochondria to damaged acceptor cells via actin-based intercellular structures. In this study, we tested the hypothesis that MSCs transfer mitochondria to neural stem cells (NSCs) to protect NSCs against the neurotoxic effects of cisplatin treatment. Our results show that MSCs donate mitochondria to NSCs damaged in vitro by cisplatin. Transfer of healthy MSC-derived mitochondria decreases cisplatin-induced NSC death. Moreover, mitochondrial transfer from MSCs to NSCs reverses the cisplatin-induced decrease in mitochondrial membrane potential. Blocking the formation of actin-based intercellular structures inhibited the transfer of mitochondria to NSCs and abrogated the positive effects of MSCs on NSC survival. Conversely, overexpression of the mitochondrial motor protein Rho-GTPase 1 (Miro1) in MSCs increased mitochondrial transfer and further improved survival of cisplatin-treated NSCs. In vivo, MSC administration prevented the loss of DCX+ neural progenitor cells in the subventricular zone and hippocampal dentate gyrus which occurs as a result of cisplatin treatment. We propose mitochondrial transfer as one of the mechanisms via which MSCs exert their therapeutic regenerative effects after cisplatin treatment.
      PubDate: 2018-12-12
       
  • Identification of TCERG1 as a new genetic modulator of TDP-43 production
           in Drosophila

    • Abstract: Abstract TAR DNA-binding protein-43 (TDP-43) is a ubiquitously expressed DNA-/RNA-binding protein that has been linked to numerous aspects of the mRNA life cycle. Similar to many RNA-binding proteins, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. Cell function and survival depend on the strict control of TDP-43 protein levels. TDP-43 has been identified as the major constituent of ubiquitin-positive inclusions in patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Several observations argue for a pathogenic role of elevated TDP-43 levels in these disorders. Modulation of the cycle of TDP-43 production might therefore provide a new therapeutic strategy. Using a Drosophila model mimicking key features of the TDP-43 autoregulatory feedback loop, we identified CG42724 as a genetic modulator of TDP-43 production in vivo. We found that CG42724 protein influences qualitatively and quantitatively the TDP-43 mRNA transcript pattern. CG42724 overexpression promotes the production of transcripts that can be efficiently released into the cytoplasm for protein translation. Importantly, we showed that TCERG1, the human homolog of the Drosophila CG42724 protein, also caused an increase of TDP-43 protein steady-state levels in mammalian cells. Therefore, our data suggest the possibility that targeting TCERG1 could be therapeutic in TDP-43 proteinopathies.
      PubDate: 2018-12-12
       
  • 5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a
           mouse model for Alzheimer’s disease

    • Abstract: Abstract Serotoninergic activation which decreases brain Aβ peptides is considered beneficial in mouse models for Alzheimer’s disease (AD), but the mechanisms involved remain unclear. Because growing evidence suggested that the stimulation of proteases digesting Aβ, especially the endopeptidase neprilysin (NEP) may be effective for AD therapy/prevention, we explored the involvement of serotonin precursors and derivatives in NEP regulation. We found that 5-hydroxyindolacetic acid (5-HIAA), the final metabolite of serotonin, considered until now as a dead-end and inactive product of serotonin catabolism, significantly reduces brain Aβ in the transgenic APPSWE mouse model for AD-related Aβ pathology and in the phosphoramidon-induced cerebral NEP inhibition mouse model. 5-HIAA treatment improves memory performance in APPSWE mice. Furthermore, 5-HIAA and its precursors increase NEP level in vivo and in neuroblastoma cells. Inhibition of ERK 1/2 cascade by 5-HIAA or SCH772984 enhanced NEP levels, suggesting MAP-kinase pathway involvement in 5-HIAA-induced regulation of NEP expression. Our results provide the first demonstration that 5-HIAA is an active serotonin metabolite that increases brain Aβ degradation/clearance and improves symptoms in the APPSWE mouse model for AD.
      PubDate: 2018-12-11
       
  • Immunological analysis of phase II glioblastoma dendritic cell vaccine
           (Audencel) trial: immune system characteristics influence outcome and
           Audencel up-regulates Th1-related immunovariables

    • Abstract: Abstract Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via “danger signals”. The recent phase II “GBM-Vax” trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel’s effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel’s general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up-regulation of the Th1-related immunovariables ELISPOT IFNγ, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNγ and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further – with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers.
      PubDate: 2018-12-05
       
  • Significance of molecular classification of ependymomas: C11orf95-RELA
           fusion-negative supratentorial ependymomas are a heterogeneous group of
           tumors

    • Abstract: Abstract Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.
      PubDate: 2018-12-04
       
  • Skeletal myopathy in Pompe disease: a failure of satellite cell
           activation'

    • PubDate: 2018-11-30
       
  • Different tau species lead to heterogeneous tau pathology propagation and
           misfolding

    • Abstract: Abstract Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer’s disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.
      PubDate: 2018-11-29
       
  • In vivo induction of membrane damage by β-amyloid peptide oligomers

    • Abstract: Abstract Exposure to the β-amyloid peptide (Aβ) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Aβ oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Aβ oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Aβ exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Aβ induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Aβ Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer’s disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Aβ multimerization and thus the formation of potentially pore-forming oligomers. We propose that Aβ-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.
      PubDate: 2018-11-29
       
  • The relevance of cerebrospinal fluid α-synuclein levels to sporadic and
           familial Alzheimer’s disease

    • Abstract: Abstract Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members. Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-β1–40. Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.
      PubDate: 2018-11-26
       
 
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