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Publisher: Biomed Central Ltd.   (Total: 291 journals)

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Showing 1 - 200 of 291 Journals sorted alphabetically
Acta Neuropathologica Communications     Open Access   (Followers: 1, SJR: 2.302, h-index: 14)
Acta Veterinaria Scandinavica     Open Access   (Followers: 3, SJR: 0.425, h-index: 37)
Addiction Science & Clinical Practice     Open Access   (Followers: 7, SJR: 0.956, h-index: 22)
Advances in Simulation     Open Access   (Followers: 2)
Agriculture & Food Security     Open Access   (Followers: 14)
AIDS Research and Therapy     Open Access   (Followers: 14, SJR: 0.839, h-index: 28)
Algorithms for Molecular Biology     Open Access   (Followers: 4, SJR: 0.97, h-index: 24)
Allergy, Asthma and Clinical Immunology     Open Access   (Followers: 25, SJR: 0.782, h-index: 17)
Alzheimer's Research & Therapy     Open Access   (Followers: 6, SJR: 2.046, h-index: 25)
Animal Biotelemetry     Open Access   (Followers: 1)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 9, SJR: 0.827, h-index: 36)
Annals of General Psychiatry     Open Access   (Followers: 22, SJR: 0.727, h-index: 32)
Annals of Occupational and Environmental Medicine     Open Access   (Followers: 9)
Annals of Surgical Innovation and Research     Open Access   (Followers: 3, SJR: 0.429, h-index: 10)
Antimicrobial Resistance and Infection Control     Open Access   (Followers: 8, SJR: 1.096, h-index: 12)
Archives of Physiotherapy     Open Access   (Followers: 10)
Archives of Public Health     Open Access   (Followers: 9, SJR: 0.974, h-index: 11)
Arthritis Research & Therapy     Open Access   (Followers: 12, SJR: 1.617, h-index: 111)
Asia Pacific Family Medicine     Open Access   (SJR: 0.227, h-index: 6)
Asthma Research and Practice     Open Access   (Followers: 1)
Basic and Clinical Andrology     Open Access   (SJR: 0.195, h-index: 7)
Behavioral and Brain Functions     Open Access   (Followers: 3, SJR: 0.989, h-index: 42)
Big Data Analytics     Open Access   (Followers: 21)
BioData Mining     Open Access   (Followers: 6, SJR: 1.331, h-index: 13)
Biological Procedures Online     Open Access   (SJR: 0.664, h-index: 31)
Biological Research     Open Access   (SJR: 0.629, h-index: 41)
Biology Direct     Open Access   (Followers: 7, SJR: 3.341, h-index: 45)
Biology of Mood & Anxiety Disorders     Open Access   (Followers: 6, SJR: 0.974, h-index: 4)
Biology of Sex Differences     Open Access   (Followers: 3, SJR: 2.25, h-index: 18)
Biomarker Research     Open Access   (Followers: 2)
Biomaterials Research     Open Access   (Followers: 4)
BioMedical Engineering OnLine     Open Access   (Followers: 7, SJR: 0.531, h-index: 44)
BioPsychoSocial Medicine     Open Access   (Followers: 6, SJR: 0.638, h-index: 20)
Biotechnology for Biofuels     Open Access   (Followers: 10, SJR: 2.557, h-index: 47)
BMC Anesthesiology     Open Access   (Followers: 16, SJR: 0.655, h-index: 23)
BMC Biochemistry     Open Access   (Followers: 14, SJR: 0.792, h-index: 38)
BMC Bioinformatics     Open Access   (Followers: 132, SJR: 1.722, h-index: 144)
BMC Biology     Open Access   (Followers: 63, SJR: 3.871, h-index: 71)
BMC Biophysics     Open Access   (Followers: 5, SJR: 0.309, h-index: 9)
BMC Biotechnology     Open Access   (Followers: 15, SJR: 0.914, h-index: 54)
BMC Cancer     Open Access   (Followers: 26, SJR: 1.627, h-index: 84)
BMC Cardiovascular Disorders     Open Access   (Followers: 21, SJR: 1.023, h-index: 37)
BMC Cell Biology     Open Access   (Followers: 49, SJR: 1.486, h-index: 48)
BMC Clinical Pathology     Open Access   (Followers: 7, SJR: 0.753, h-index: 24)
BMC Complementary and Alternative Medicine     Open Access   (Followers: 13, SJR: 0.783, h-index: 53)
BMC Dermatology     Open Access   (Followers: 12, SJR: 0.854, h-index: 27)
BMC Developmental Biology     Open Access   (Followers: 14, SJR: 1.38, h-index: 55)
BMC Ear, Nose and Throat Disorders     Open Access   (Followers: 1, SJR: 0.636, h-index: 15)
BMC Ecology     Open Access   (Followers: 19, SJR: 1.433, h-index: 27)
BMC Emergency Medicine     Open Access   (Followers: 16, SJR: 0.679, h-index: 22)
BMC Endocrine Disorders     Open Access   (Followers: 6, SJR: 0.733, h-index: 25)
BMC Evolutionary Biology     Open Access   (Followers: 76, SJR: 2.053, h-index: 83)
BMC Family Practice     Open Access   (Followers: 12, SJR: 0.978, h-index: 42)
BMC Gastroenterology     Open Access   (Followers: 15, SJR: 0.999, h-index: 50)
BMC Genetics     Open Access   (Followers: 24, SJR: 1.185, h-index: 51)
BMC Genomics     Open Access   (Followers: 91, SJR: 2.343, h-index: 108)
BMC Geriatrics     Open Access   (Followers: 14, SJR: 1.025, h-index: 41)
BMC Health Services Research     Open Access   (Followers: 15, SJR: 1.128, h-index: 64)
BMC Hematology     Open Access   (Followers: 3)
BMC Immunology     Open Access   (Followers: 10, SJR: 1.087, h-index: 38)
BMC Infectious Diseases     Open Access   (Followers: 16, SJR: 1.51, h-index: 66)
BMC Intl. Health and Human Rights     Open Access   (Followers: 6, SJR: 0.878, h-index: 26)
BMC Medical Education     Open Access   (Followers: 41, SJR: 0.698, h-index: 38)
BMC Medical Ethics     Open Access   (Followers: 16, SJR: 0.859, h-index: 26)
BMC Medical Genetics     Open Access   (Followers: 7, SJR: 1.062, h-index: 52)
BMC Medical Genomics     Open Access   (Followers: 6, SJR: 1.71, h-index: 37)
BMC Medical Imaging     Open Access   (Followers: 8, SJR: 0.651, h-index: 22)
BMC Medical Informatics and Decision Making     Open Access   (Followers: 23, SJR: 1.1, h-index: 44)
BMC Medical Physics     Open Access   (Followers: 5, SJR: 0.564, h-index: 13)
BMC Medical Research Methodology     Open Access   (Followers: 8, SJR: 1.788, h-index: 67)
BMC Medicine     Open Access   (Followers: 13, SJR: 3.415, h-index: 72)
BMC Microbiology     Open Access   (Followers: 11, SJR: 1.391, h-index: 74)
BMC Molecular Biology     Open Access   (Followers: 129, SJR: 1.224, h-index: 53)
BMC Musculoskeletal Disorders     Open Access   (Followers: 17, SJR: 0.881, h-index: 61)
BMC Nephrology     Open Access   (Followers: 10, SJR: 1.113, h-index: 29)
BMC Neurology     Open Access   (Followers: 21, SJR: 1.07, h-index: 45)
BMC Neuroscience     Open Access   (Followers: 16, SJR: 1.318, h-index: 70)
BMC Nursing     Open Access   (Followers: 22, SJR: 0.561, h-index: 20)
BMC Nutrition     Open Access   (Followers: 8)
BMC Obesity     Open Access   (Followers: 6)
BMC Ophthalmology     Open Access   (Followers: 15, SJR: 0.938, h-index: 29)
BMC Oral Health     Open Access   (Followers: 5, SJR: 0.616, h-index: 28)
BMC Palliative Care     Open Access   (Followers: 23, SJR: 1.003, h-index: 25)
BMC Pediatrics     Open Access   (Followers: 15, SJR: 1.097, h-index: 47)
BMC Pharmacology     Open Access   (Followers: 3, SJR: 0.739, h-index: 30)
BMC Pharmacology & Toxicology     Open Access   (Followers: 8, SJR: 0.792, h-index: 10)
BMC Physiology     Open Access   (Followers: 4, SJR: 0.996, h-index: 30)
BMC Plant Biology     Open Access   (Followers: 14, SJR: 1.945, h-index: 71)
BMC Pregnancy and Childbirth     Open Access   (Followers: 20, SJR: 1.397, h-index: 45)
BMC Proceedings     Full-text available via subscription   (Followers: 2, SJR: 0.445, h-index: 9)
BMC Psychiatry     Open Access   (Followers: 27, SJR: 1.307, h-index: 57)
BMC Psychology     Open Access   (Followers: 17)
BMC Public Health     Open Access   (Followers: 148, SJR: 1.372, h-index: 81)
BMC Pulmonary Medicine     Open Access   (Followers: 4, SJR: 1.011, h-index: 38)
BMC Research Notes     Open Access   (Followers: 5, SJR: 0.702, h-index: 38)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 26, SJR: 0.471, h-index: 7)
BMC Structural Biology     Open Access   (Followers: 8, SJR: 1.118, h-index: 42)
BMC Surgery     Open Access   (Followers: 9, SJR: 0.675, h-index: 31)
BMC Systems Biology     Open Access   (Followers: 12, SJR: 1.493, h-index: 52)
BMC Urology     Open Access   (Followers: 14, SJR: 0.719, h-index: 27)
BMC Veterinary Research     Open Access   (Followers: 12, SJR: 0.952, h-index: 31)
BMC Women's Health     Open Access   (Followers: 10, SJR: 0.746, h-index: 30)
BMC Zoology     Open Access  
Borderline Personality Disorder and Emotion Dysregulation     Open Access   (Followers: 10)
Breast Cancer Research     Open Access   (Followers: 18, SJR: 3.133, h-index: 107)
Burns & Trauma     Open Access   (Followers: 2)
Burns & Trauma     Open Access   (Followers: 10)
Cancer & Metabolism     Open Access   (Followers: 5)
Cancer Cell Intl.     Open Access   (Followers: 4, SJR: 1.05, h-index: 33)
Cancer Imaging     Open Access   (Followers: 2, SJR: 0.67, h-index: 30)
Cancers of the Head & Neck     Open Access  
Canine Genetics and Epidemiology     Open Access   (Followers: 1)
Cardio-Oncology     Open Access  
Cardiovascular Diabetology     Open Access   (Followers: 9, SJR: 1.757, h-index: 47)
Cardiovascular Ultrasound     Open Access   (Followers: 4, SJR: 0.65, h-index: 31)
Cell Communication and Signaling     Open Access   (Followers: 2, SJR: 1.86, h-index: 37)
Cell Division     Open Access   (Followers: 1, SJR: 2.011, h-index: 32)
Cellular & Molecular Biology Letters     Hybrid Journal   (Followers: 3)
Cerebellum & Ataxias     Open Access   (Followers: 1)
Child and Adolescent Psychiatry and Mental Health     Open Access   (Followers: 22, SJR: 1.25, h-index: 25)
Chinese Medicine     Open Access   (Followers: 2, SJR: 0.655, h-index: 24)
Chinese Neurosurgical J.     Open Access  
Chiropractic & Manual Therapies     Open Access   (Followers: 5, SJR: 0.575, h-index: 19)
Cilia     Open Access   (SJR: 3.69, h-index: 12)
Clinical and Molecular Allergy     Open Access   (Followers: 5, SJR: 0.871, h-index: 24)
Clinical and Translational Allergy     Open Access   (Followers: 2, SJR: 0.119, h-index: 2)
Clinical Diabetes and Endocrinology     Open Access   (Followers: 12)
Clinical Hypertension     Open Access   (Followers: 3)
Clinical Sarcoma Research     Open Access  
Conflict and Health     Open Access   (Followers: 8, SJR: 0.831, h-index: 12)
Contraception and Reproductive Medicine     Open Access  
COPD Research and Practice     Open Access  
Cost Effectiveness and Resource Allocation     Open Access   (Followers: 4, SJR: 0.767, h-index: 26)
Critical Care     Open Access   (Followers: 53, SJR: 2.002, h-index: 112)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 18)
Diabetology & Metabolic Syndrome     Open Access   (Followers: 8, SJR: 0.834, h-index: 23)
Diagnostic Pathology     Open Access   (Followers: 7, SJR: 0.775, h-index: 29)
Disaster and Military Medicine     Open Access   (Followers: 3)
Emerging Themes in Epidemiology     Open Access   (Followers: 13, SJR: 1.172, h-index: 24)
Environmental Health     Open Access   (Followers: 11, SJR: 1.898, h-index: 51)
Epigenetics & Chromatin     Open Access   (Followers: 8, SJR: 4.614, h-index: 26)
European J. of Medical Research     Open Access   (Followers: 1, SJR: 0.592, h-index: 46)
European Review of Aging and Physical Activity     Open Access   (Followers: 8, SJR: 0.597, h-index: 14)
Experimental & Translational Stroke Medicine     Open Access   (Followers: 8, SJR: 0.644, h-index: 13)
Experimental Hematology & Oncology     Open Access   (Followers: 3)
Eye and Vision     Open Access   (Followers: 1)
Fertility Research and Practice     Open Access   (Followers: 1)
Fibrogenesis & Tissue Repair     Open Access   (SJR: 2.496, h-index: 27)
Fisheries and Aquatic Sciences     Open Access   (Followers: 2, SJR: 0.223, h-index: 8)
Flavour     Open Access   (Followers: 4)
Fluids and Barriers of the CNS     Open Access   (Followers: 2, SJR: 2.034, h-index: 29)
Frontiers in Zoology     Open Access   (Followers: 6, SJR: 1.866, h-index: 37)
Genes and Environment     Open Access   (SJR: 0.161, h-index: 5)
Genetics Selection Evolution     Open Access   (Followers: 7, SJR: 1.341, h-index: 55)
Genome Biology     Open Access   (Followers: 29, SJR: 9.86, h-index: 168)
Genome Medicine     Open Access   (Followers: 7, SJR: 2.915, h-index: 40)
Global Health Research and Policy     Open Access   (Followers: 2)
Globalization and Health     Open Access   (Followers: 5, SJR: 1.261, h-index: 29)
Gut Pathogens     Full-text available via subscription   (Followers: 5, SJR: 1.136, h-index: 18)
Gynecologic Oncology Research and Practice     Open Access   (Followers: 1)
Harm Reduction J.     Open Access   (SJR: 1.239, h-index: 31)
Head & Face Medicine     Open Access   (Followers: 1, SJR: 0.416, h-index: 22)
Health and Quality of Life Outcomes     Open Access   (Followers: 13, SJR: 1.02, h-index: 75)
Health Research Policy and Systems     Open Access   (Followers: 11, SJR: 1.032, h-index: 28)
Hereditary Cancer in Clinical Practice     Open Access   (SJR: 0.678, h-index: 14)
Hereditas     Open Access   (Followers: 2, SJR: 0.423, h-index: 40)
Human Genomics     Open Access   (Followers: 3, SJR: 1.632, h-index: 35)
Human Resources for Health     Open Access   (Followers: 8, SJR: 1.193, h-index: 38)
Immunity & Ageing     Open Access   (Followers: 10, SJR: 1.178, h-index: 28)
Implementation Science     Open Access   (Followers: 15, SJR: 2.259, h-index: 53)
Infectious Agents and Cancer     Open Access   (SJR: 1.085, h-index: 21)
Infectious Diseases of Poverty     Open Access   (Followers: 2, SJR: 0.977, h-index: 12)
Inflammation and Regeneration     Open Access   (Followers: 1)
Intl. Breastfeeding J.     Open Access   (Followers: 22, SJR: 0.934, h-index: 23)
Intl. J. for Equity in Health     Open Access   (Followers: 7, SJR: 1.316, h-index: 31)
Intl. J. of Behavioral Nutrition and Physical Activity     Open Access   (Followers: 24, SJR: 2.216, h-index: 64)
Intl. J. of Health Geographics     Open Access   (Followers: 6, SJR: 1.216, h-index: 48)
Intl. J. of Mental Health Systems     Open Access   (Followers: 7, SJR: 0.484, h-index: 18)
Intl. J. of Pediatric Endocrinology     Open Access   (Followers: 10)
Intl. J. of Retina and Vitreous     Open Access   (Followers: 2)
Investigative Genetics     Open Access   (Followers: 1, SJR: 0.98, h-index: 13)
Irish Veterinary J.     Open Access   (Followers: 6, SJR: 0.477, h-index: 17)
Israel J. of Health Policy Research     Open Access   (SJR: 0.379, h-index: 7)
Italian J. of Pediatrics     Open Access   (Followers: 1, SJR: 0.685, h-index: 20)
J. for ImmunoTherapy of Cancer     Open Access   (Followers: 5)
J. of Angiogenesis Research     Open Access   (Followers: 2)
J. of Animal Science and Biotechnology     Open Access   (Followers: 6, SJR: 0.87, h-index: 10)
J. of Animal Science and Technology     Open Access   (Followers: 2)
J. of Biological Engineering     Open Access   (Followers: 4, SJR: 1.104, h-index: 22)
J. of Biological Research - Thessaloniki     Open Access   (SJR: 0.273, h-index: 10)
J. of Biomedical Semantics     Open Access   (Followers: 2, SJR: 0.903, h-index: 18)
J. of Cardiothoracic Surgery     Open Access   (Followers: 4, SJR: 0.622, h-index: 26)
J. of Cardiovascular Magnetic Resonance     Open Access   (Followers: 1, SJR: 3.238, h-index: 58)
J. of Clinical Movement Disorders     Open Access   (Followers: 3)
J. of Congenital Cardiology     Open Access   (Followers: 3)
J. of Diabetes and Metabolic Disorders     Open Access   (Followers: 9, SJR: 0.693, h-index: 9)
J. of Eating Disorders     Open Access   (Followers: 8, SJR: 1.047, h-index: 7)
J. of Environmental Health Science & Engineering     Open Access   (Followers: 1, SJR: 0.45, h-index: 17)
J. of Ethnobiology and Ethnomedicine     Open Access   (SJR: 1.001, h-index: 40)
J. of Experimental & Clinical Cancer Research     Open Access   (Followers: 2, SJR: 1.702, h-index: 51)

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Journal Cover Acta Neuropathologica Communications
  [SJR: 2.302]   [H-I: 14]   [1 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2051-5960
   Published by Biomed Central Ltd. Homepage  [291 journals]
  • Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an
           international study

    • Abstract: Abstract The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts. To investigate this phenomenon further, a cohort of 27 iCJD cases – 21 with adequate number of histopathological sections – originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrPSc), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND). Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrPSc with the exception of iCJD harboring the “MMi” phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients’ younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD. In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.
      PubDate: 2018-01-08
       
  • Surfen, a proteoglycan binding agent, reduces inflammation but inhibits
           remyelination in murine models of Multiple Sclerosis

    • Abstract: Abstract Proteoglycans are promising therapeutic targets in Multiple Sclerosis (MS), because they regulate many aspects of the immune response. This was studied using surfen, an agent that binds both heparan sulphate proteoglycans (HSPGs) and chondroitin sulphate proteoglycans (CSPGs). Initial cell culture work on bone marrow derived macrophages (BMDMs) found that surfen reduced concentrations of the chemokines CCL2, CCL4 and CCL5, with reduced messenger (m)RNA expression for Tumor Necrosis Factor, IL-6, IL-1β and inducible nitric oxide synthase. These data were further explored using Experimental Autoimmune Encephalomyelitis (EAE) in mice. Surfen reduced clinical signs during EAE when administered from disease onset, and reduced infiltration by CD4 positive T cells and macrophages into the central nervous system. These mice also showed reduced mRNA expression for the chemokines CCL3 and CCL5, with reduced concentrations of CCL2, CCL3 and CCL5. During EAE, surfen treatment induced a persistent increase in Interleukin (IL)-4 concentrations which may enhance T helper 2 responses. During EAE, surfen treatment reduced mRNA expression for HSPGs (NDST1, agrin, syndecan-4, perlecan, serglycin, syndecan-1) and the CSPG versican. By contrast, surfen increased mRNA expression for the CSPG aggrecan, with no effect on neurocan. During EAE, significant positive correlations were found between mRNA expression and clinical score for syndecan-4, serglycin and syndecan-1 and a significant negative correlation for aggrecan. These correlations were absent in surfen treated mice. Repair in the later stages of MS involves remyelination, which was modeled by injecting lysolecithin (lysophosphatidylcholine, LPC) into mouse corpus callosum to create regions of demyelination. When surfen was injected 2 days after LPC, it delayed remyelination of the lesions, but had no effect when injected 7 days after LPC. The delayed remyelination was associated with local increases in CSPG expression. Therefore surfen suppresses inflammation but inhibits remyelination in these models. A mechanism in common may be increased CSPG expression.
      PubDate: 2018-01-04
       
  • Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and
           Alzheimer’s disease

    • Abstract: Abstract Alzheimer’s disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation. In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a characteristic deposition of IsoD-Aβ in blood vessel walls and pE3-Aβ within neurons. Both AD and OC showed positive associations between IsoD-Aβ and Aβ (p = 0.003 in AD and p = 0.001 in OC) and between IsoD-Aβ and pE3-Aβ (p = 0.001 in AD and OC). This last association was the only significant pE3-Aβ correlation identified in AD, whereas in the control cohorts pE3-Aβ also correlated with Aβ and AβPP (p = 0.001 in OC and p = 0.010 in YC). Our analyses suggest that IsoD-Aβ accumulation starts with ageing; whereas pE3-Aβ deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aβ in AD pathogenesis.
      PubDate: 2018-01-03
       
  • Brainstem tau pathology in Alzheimer’s disease is characterized by
           increase of three repeat tau and independent of amyloid β

    • Abstract: Introduction Alzheimer-type neuropil threads (NTs) and neurofibrillary tangles (NFTs) are comprised of either 4 repeat (4R)-tau, 3 repeat (3R)-tau, or a mixture of both. In the hippocampus, the number of NFTs, and the proportion of 3R tau progressively increases. If this preferential accumulation of 3R tau also occurs in the brainstem, it may be fundamentally related to progression of Alzheimer pathology. Methods Midbrain and pontine sections of brainstems from 23 cases (Braak-NFT stages I/II: 8, III/IV: 8, and V/VI: 7) were double immunofluorolabeled for 4R and 3R tau. High-resolution (0.645 μm/pixel), in-focus snapshots were tiled to cover entire brain sections using a virtual slide system. Each lesion was classified by size (NT < 200 μm2 < NFT) and staining profile (3R/4R). In addition, the localization and quantity of amyloid β (Aβ) deposits were examined in adjacent sections for comparison with tau. Results The data sets obtained from approximately 286 gigabytes of image files consisted of 847,763 NTs and 7859 NFTs. The proportion of 3R tau-positive NTs and NFTs in the midbrain, and 3R tau-positive NTs in the pons gradually increased with advancing NFT stages, while the proportion of 3R tau-positive NFTs in the pons was already elevated at early stages. Aβ deposits were absent at NFT stages I/II, and when present at later stages, their regional distribution was different from that of tau. These observations suggest that a progressive increase in the proportion of 3R tau occurs independently of Aβ deposits. Conclusions This is the first quantitative analysis of NFTs and NTs in the human brainstem. We demonstrate that the proportion of 3R tau in the brainstem neurofibrillary changes increases with disease progression. Because this phenomenon is shared between the brainstem and the hippocampus, this increase may be fundamental to the pathogenesis of Alzheimer disease.
      PubDate: 2018-01-03
       
  • Progressive striatonigral degeneration in a transgenic mouse model of
           multiple system atrophy: translational implications for interventional
           therapies

    • Abstract: Abstract Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
      PubDate: 2018-01-03
       
  • What is the evidence that tau pathology spreads through prion-like
           propagation'

    • Abstract: Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a “prion-like” mechanism involving transfer of abnormal tau seeds from a “donor cell” to a “recipient cell” and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a “prion-like” mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and “prion-like” propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using “prion-like” mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so far not been shown to exhibit all of these steps and how this influences the debate of whether or not abnormal tau species can propagate in a “prion-like” manner is discussed. The exact nature of tau seeds responsible for propagation of tau pathology in human tauopathies remains controversial; it might be tightly linked to the existence of tau strains stably propagating peculiar patterns of neuropathological lesions, corresponding to the different patterns seen in human tauopathies. That this is a property shared by all seed-competent tau conformers is not yet firmly established. Further investigation is also required to clarify the relationship between propagation of tau aggregates and tau-induced toxicity. Genetic variants identified as risks factors for tauopathies might play a role in propagation of tau pathology, but many more studies are needed to document this. The contribution of selective vulnerability of neuronal populations, as an alternative to prion-like mechanisms to explain spreading of tau pathology needs to be clarified. Learning from the prion field will be helpful to enhance our understanding of propagation of tau pathology. Finally, development of better models is expected to answer some of these key questions and allow for the testing of propagation-centred therapies.
      PubDate: 2017-12-19
       
  • Absence of MGMT promoter methylation in diffuse midline glioma, H3
           K27M-mutant

    • PubDate: 2017-12-15
       
  • Retraction Note: Transgenic mice overexpressing the ALS-linked protein
           Matrin 3 develop a profound muscle phenotype

    • Abstract: The authors are retracting this article. The article describes mice expressing wild-type human MATR3. However, since publication the authors have become aware that all of the lines of mice described express human MATR3 containing the F115C mutation. Transgenic mice expressing wild-type and mutant Matrin were created simultaneously in their laboratory and, at a crucial stage of generating the DNA for embryo injection, as confirmed by an investigation by the University of Florida, the DNA preparations were accidentally mislabelled. All of the founders created were mosaic, requiring extensive breeding to isolate stable lines. Mice mislabelled as expressing wild-type MATR3 were the first to produce lines that stably transmitted the transgene and thus were the first to be characterized. However, as lines of mice that were mislabelled as expressing the mutant (F115C) MATR3 were ultimately established, the data began to suggest that an error had been made. Sequence analysis of amplified tail DNA from mice descended from the lines reported in the article have revealed that they express the F115C variant. The data described are therefore an accurate description of the pathology of mice that express the F115C variant of MATR3, but not of mice expressing wild-type MATR3. The authors are preparing a new manuscript reporting data from both mice expressing the F115C variant of MATR3 and mice expressing wild-type MATR3.
      PubDate: 2017-12-13
       
  • Clinical and neuropathological features of ALS/FTD with TIA1 mutations

    • Abstract: Abstract Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.
      PubDate: 2017-12-07
       
  • Metabolomics reveals distinct, antibody-independent, molecular signatures
           of MS, AQP4-antibody and MOG-antibody disease

    • Abstract: The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not prognostic and may become undetectable after treatment or during remission. Therefore, there is still a need to discover antibody-independent biomarkers. We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre. Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling. Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases. In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease. In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%. The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease. RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol. Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level. The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis.
      PubDate: 2017-12-06
       
  • Cerebrovascular pathology in Down syndrome and Alzheimer disease

    • Abstract: Abstract People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD) with age. Typically, by age 40 years, most people with DS have sufficient neuropathology for an AD diagnosis. Interestingly, atherosclerosis and hypertension are atypical in DS with age, suggesting the lack of these vascular risk factors may be associated with reduced cerebrovascular pathology. However, because the extra copy of APP leads to increased beta-amyloid peptide (Aβ) accumulation in DS, we hypothesized that there would be more extensive and widespread cerebral amyloid angiopathy (CAA) with age in DS relative to sporadic AD. To test this hypothesis CAA, atherosclerosis and arteriolosclerosis were used as measures of cerebrovascular pathology and compared in post mortem tissue from individuals with DS (n = 32), sporadic AD (n = 80) and controls (n = 37). CAA was observed with significantly higher frequencies in brains of individuals with DS compared to sporadic AD and controls. Atherosclerosis and arteriolosclerosis were rare in the cases with DS. CAA in DS may be a target for future interventional clinical trials.
      PubDate: 2017-12-01
       
  • Blood-brain barrier hyperpermeability precedes demyelination in the
           cuprizone model

    • Abstract: Abstract In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.
      PubDate: 2017-12-01
       
  • MUNC18–1 gene abnormalities are involved in neurodevelopmental disorders
           through defective cortical architecture during brain development

    • Abstract: Abstract While Munc18–1 interacts with Syntaxin1 and controls the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex to regulate presynaptic vesicle fusion in developed neurons, this molecule is likely to be involved in brain development since its gene abnormalities cause early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome), neonatal epileptic encephalopathy and other neurodevelopmental disorders. We thus analyzed physiological significance of Munc18–1 during cortical development. Munc18–1-knockdown impaired cortical neuron positioning during mouse corticogenesis. Time-lapse imaging revealed that the mispositioning was attributable to defects in radial migration in the intermediate zone and cortical plate. Notably, Syntaxin1A was critical for radial migration downstream of Munc18–1. As for the underlying mechanism, Munc18–1-knockdown in cortical neurons hampered post-Golgi vesicle trafficking and subsequent vesicle fusion at the plasma membrane in vivo and in vitro, respectively. Notably, Syntaxin1A-silencing did not affect the post-Golgi vesicle trafficking. Taken together, Munc18–1 was suggested to regulate radial migration by modulating not only vesicle fusion at the plasma membrane to distribute various proteins on the cell surface for interaction with radial fibers, but also preceding vesicle transport from Golgi to the plasma membrane. Although knockdown experiments suggested that Syntaxin1A does not participate in the vesicle trafficking, it was supposed to regulate subsequent vesicle fusion under the control of Munc18–1. These observations may shed light on the mechanism governing radial migration of cortical neurons. Disruption of Munc18–1 function may result in the abnormal corticogenesis, leading to neurodevelopmental disorders with MUNC18–1 gene abnormalities.
      PubDate: 2017-11-30
       
  • EuroTau: towing scientists to tau without tautology

    • PubDate: 2017-11-29
       
  • Atypical, non-standard functions of the microtubule associated Tau protein

    • Abstract: Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau’s role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system.
      PubDate: 2017-11-29
       
  • Astrocytes in mouse models of tauopathies acquire early deficits and lose
           neurosupportive functions

    • Abstract: Abstract Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of several neurodegenerative diseases grouped under the name of tauopathies. It is now clear that the process of tau aggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed where tau progressively aggregates, causing neuronal death. Previously we have shown that transplantation of astrocytes in P301S tau transgenic mice rescues cortical neuron death, implying that the endogenous astrocytes are deficient in survival support. We now show that the gliosis markers Glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β) are elevated in brains from P301S tau mice compared to control C57Bl/6 mice whereas the expression of proteins involved in glutamine/glutamate metabolism are reduced, pointing to a functional deficit. To test whether astrocytes from P301S mice are intrinsically deficient, we co-cultured astrocytes and neurons from control and P301S mice. Significantly more C57-derived and P301S-derived neurons survived when cells were cultured with C57-derived astrocytes or astrocyte conditioned medium (C57ACM) than with P301S-derived astrocytes or astrocyte conditioned medium (P301SACM), or ACM from P301L tau mice, where the transgene is also specifically expressed in neurons. The astrocytic alterations developed in mice during the first postnatal week of life. In addition, P301SACM significantly decreased presynaptic (synaptophysin, SNP) and postsynaptic (postsynaptic density protein 95, PSD95) protein expression in cortical neuron cultures whereas C57ACM enhanced these markers. Since thrombospondin 1 (TSP-1) is a major survival and synaptogenic factor, we examined whether TSP-1 is deficient in P301S mouse brains and ACM. Significantly less TSP-1 was expressed in the brains of P301S tau mice or produced by P301S-derived astrocytes, whereas supplementation of P301SACM with TSP-1 increased its neurosupportive capacity. Our results demonstrate that P301S-derived astrocytes acquire an early functional deficiency that may explain in part the loss of cortical neurons in the P301S tau mice.
      PubDate: 2017-11-29
       
  • The chronically inflamed central nervous system provides niches for
           long-lived plasma cells

    • Abstract: Abstract Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138+Ki67−) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2′-deoxyuridine (EdU). Up to five weeks later, we could detect EdU+ long-lived plasma cells in the murine CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.
      PubDate: 2017-11-25
       
  • Atypical Creutzfeldt-Jakob disease with PrP-amyloid plaques in white
           matter: molecular characterization and transmission to bank voles show the
           M1 strain signature

    • Abstract: Abstract Amyloid plaques formed by abnormal prion protein (PrPSc) aggregates occur with low frequency in Creutzfeldt-Jakob disease, but represent a pathological hallmark of three relatively rare disease histotypes, namely variant CJD, sporadic CJDMV2K (methionine/valine at PRNP codon 129, PrPSc type 2 and kuru-type amyloid plaques) and iatrogenic CJDMMiK (MM at codon 129, PrPSc of intermediate type and kuru plaques). According to recent studies, however, PrP-amyloid plaques involving the subcortical and deep nuclei white matter may also rarely occur in CJDMM1 (MM at codon 129 and PrPSc type 1), the most common CJD histotype. To further characterize the phenotype of atypical CJDMM1 with white matter plaques (p-CJDMM1) and unravel the basis of amyloid plaque formation in such cases, we compared clinical and histopathological features and PrPSc physico-chemical properties between 5 p-CJDMM1 and 8 typical CJDMM1 brains lacking plaques. Furthermore, transmission properties after bioassay in two genetic lines of bank voles were also explored in the two groups. All 5 p-CJDMM1 cases had a disease duration longer than one year. Three cases were classified as sporadic CJDMM1, one as sporadic CJDMM1 + 2C and one as genetic CJDE200K-MM1. Molecular mass, protease sensitivity and thermo-solubilization of PrPSc aggregates did not differ between p-CJDMM1 and classical CJDMM1 cases. Likewise, transmission properties such as incubation time, lesion profile and PrPSc properties in bank voles also matched in the two groups. The present data further define the clinical-pathologic phenotype of p-CJDMM1, definitely establish it as a distinctive CJD histotype and demonstrate that PrP-plaque formation in this histotype is not a strain-specific feature. Since cases lacking amyloid plaques may also manifest a prolonged (i.e. > than one year) disease course, unidentified, host-specific factors likely play a significant role, in addition to disease duration, in generating white matter PrP-amyloid plaques in p-CJDMM1.
      PubDate: 2017-11-23
       
  • Elevated LRRK2 autophosphorylation in brain-derived and peripheral
           exosomes in LRRK2 mutation carriers

    • Abstract: Abstract Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease (PD). LRRK2 mutations increase LRRK2 kinase activities that may increase levels of LRRK2 autophosphorylation at serine 1292 (pS1292) and neurotoxicity in model systems. pS1292-LRRK2 protein can be packaged into exosomes and measured in biobanked urine. Herein we provide evidence that pS1292-LRRK2 protein is robustly expressed in cerebral spinal fluid (CSF) exosomes. In a novel cohort of Norwegian subjects with and without the G2019S-LRRK2 mutation, with and without PD, we quantified levels of pS1292-LRRK2, total LRRK2, and other exosome proteins in urine from 132 subjects and in CSF from 82 subjects. CSF and urine were collected from the same morning clinic visit in 55 of the participants. We found that total LRRK2 protein concentration was similar in exosomes purified from either CSF or urine but the levels did not correlate. pS1292-LRRK2 levels were higher in urinary exosomes from male and female subjects with a LRRK2 mutation. Male LRRK2 mutation carriers without PD had intermediate pS1292-LRRK2 levels compared to male carriers with PD and controls. However, female LRRK2 mutation carriers without PD had the same pS1292-LRRK2 levels compared to female carriers with PD. pS1292-LRRK2 levels in CSF exosomes were near saturated in most subjects, ten-fold higher on average than pS1292-LRRK2 levels in urinary exosomes, irrespective of LRRK2 mutation status or PD diagnosis. These results provide insights into the effects of LRRK2 mutations in both the periphery and brain in a well-characterized clinical population and show that LRRK2 protein in brain exosomes may be much more active than in the periphery in most subjects.
      PubDate: 2017-11-22
       
  • α-Synuclein fibrils recruit peripheral immune cells in the rat brain
           prior to neurodegeneration

    • Abstract: Abstract Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII-expressing immune cells in the brain correlates with α-synuclein inclusions. However, the timing of MHCII-cell recruitment with respect to ongoing neurodegeneration, and the types of cells that express MHCII in the PD brain, has been difficult to understand. Recent studies show that the injection of short α-synuclein fibrils into the rat substantia nigra pars compacta (SNpc) induces progressive inclusion formation in SNpc neurons that eventually spread to spiny projection neurons in the striatum. Herein, we find that α-synuclein fibrils rapidly provoke a persistent MHCII response in the brain. In contrast, equivalent amounts of monomeric α-synuclein fail to induce MHCII or persistent microglial activation, consistent with our results in primary microglia. Flow cytometry and immunohistochemical analyses reveal that MHCII-expressing cells are composed of both resident microglia as well as cells from the periphery that include monocytes, macrophages, and lymphocytes. Over time, α-Synuclein fibril exposures in the SNpc causes both axon loss as well as monocyte recruitment in the striatum. While these monocytes in the striatum initially lack MHCII expression, α-synuclein inclusions later form in nearby spiny projection neurons and MHCII expression becomes robust. In summary, in the rat α-synuclein fibril model, peripheral immune cell recruitment occurs prior to neurodegeneration and microglia, monocytes and macrophages all contribute to MHCII expression.
      PubDate: 2017-11-21
       
 
 
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