Publisher: BMC (Biomed Central)   (Total: 308 journals)

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Showing 1 - 200 of 308 Journals sorted alphabetically
Acta Neuropathologica Communications     Open Access   (Followers: 1, SJR: 2.683, CiteScore: 5)
Acta Veterinaria Scandinavica     Open Access   (Followers: 4, SJR: 0.655, CiteScore: 1)
Addiction Science & Clinical Practice     Open Access   (Followers: 11, SJR: 1.224, CiteScore: 3)
Advances in Simulation     Open Access   (Followers: 7)
Agriculture & Food Security     Open Access   (Followers: 29, SJR: 0.575, CiteScore: 2)
AIDS Research and Therapy     Open Access   (Followers: 16, SJR: 1.08, CiteScore: 2)
Algorithms for Molecular Biology     Open Access   (Followers: 4, SJR: 1.333, CiteScore: 2)
Allergy, Asthma and Clinical Immunology     Open Access   (Followers: 29, SJR: 0.732, CiteScore: 2)
Alzheimer's Research & Therapy     Open Access   (Followers: 5, SJR: 2.449, CiteScore: 6)
Animal Biotelemetry     Open Access   (Followers: 2, SJR: 1.067, CiteScore: 2)
Animal Diseases     Open Access  
Animal Microbiome     Open Access   (Followers: 3)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 13, SJR: 1.104, CiteScore: 3)
Annals of General Psychiatry     Open Access   (Followers: 28, SJR: 0.784, CiteScore: 2)
Annals of Occupational and Environmental Medicine     Open Access   (Followers: 15, SJR: 0.452, CiteScore: 1)
Annals of Surgical Innovation and Research     Open Access   (Followers: 3, SJR: 0.328, CiteScore: 1)
Antimicrobial Resistance and Infection Control     Open Access   (Followers: 13, SJR: 1.573, CiteScore: 3)
Archives of Physiotherapy     Open Access   (Followers: 20)
Archives of Public Health     Open Access   (Followers: 13, SJR: 1.244, CiteScore: 3)
Arthritis Research & Therapy     Open Access   (Followers: 18, SJR: 2.154, CiteScore: 4)
Asthma Research and Practice     Open Access   (Followers: 2)
Basic and Clinical Andrology     Open Access   (SJR: 0.564, CiteScore: 2)
Behavioral and Brain Functions     Open Access   (Followers: 5, SJR: 0.986, CiteScore: 3)
Big Data Analytics     Open Access   (Followers: 34)
BioData Mining     Open Access   (Followers: 5, SJR: 0.982, CiteScore: 2)
Bioelectronic Medicine     Open Access   (Followers: 1)
Biological Procedures Online     Open Access   (SJR: 1.352, CiteScore: 4)
Biological Research     Open Access   (Followers: 1, SJR: 0.654, CiteScore: 2)
Biology Direct     Open Access   (Followers: 10, SJR: 1.694, CiteScore: 3)
Biology of Sex Differences     Open Access   (Followers: 2, SJR: 1.902, CiteScore: 4)
Biomarker Research     Open Access   (Followers: 3)
Biomaterials Research     Open Access   (Followers: 6, SJR: 0.735, CiteScore: 3)
Biomedical Dermatology     Open Access  
BioMedical Engineering OnLine     Open Access   (Followers: 7, SJR: 0.542, CiteScore: 2)
BioPsychoSocial Medicine     Open Access   (Followers: 9, SJR: 0.416, CiteScore: 1)
Biotechnology for Biofuels     Open Access   (Followers: 9, SJR: 1.899, CiteScore: 6)
BMC Anesthesiology     Open Access   (Followers: 18, SJR: 0.807, CiteScore: 2)
BMC Biochemistry     Open Access   (Followers: 15, SJR: 0.708, CiteScore: 2)
BMC Bioinformatics     Open Access   (Followers: 216, SJR: 1.479, CiteScore: 2)
BMC Biology     Open Access   (Followers: 63, SJR: 3.842, CiteScore: 5)
BMC Biomedical Engineering     Open Access  
BMC Biophysics     Open Access   (Followers: 4, SJR: 0.682, CiteScore: 2)
BMC Biotechnology     Open Access   (Followers: 17, SJR: 1.012, CiteScore: 3)
BMC Cancer     Open Access   (Followers: 34, SJR: 1.464, CiteScore: 3)
BMC Cardiovascular Disorders     Open Access   (Followers: 25, SJR: 0.909, CiteScore: 2)
BMC Chemical Engineering     Open Access  
BMC Clinical Pathology     Open Access   (Followers: 8, SJR: 1.141, CiteScore: 3)
BMC Complementary Medicine and Therapies     Open Access   (Followers: 24, SJR: 0.858, CiteScore: 3)
BMC Dermatology     Open Access   (Followers: 14, SJR: 0.796, CiteScore: 2)
BMC Developmental Biology     Open Access   (Followers: 14, SJR: 1.43, CiteScore: 2)
BMC Ear, Nose and Throat Disorders     Open Access   (Followers: 1, SJR: 0.653, CiteScore: 2)
BMC Ecology     Open Access   (Followers: 24, SJR: 1.076, CiteScore: 2)
BMC Emergency Medicine     Open Access   (Followers: 25, SJR: 0.572, CiteScore: 1)
BMC Endocrine Disorders     Open Access   (Followers: 7, SJR: 0.965, CiteScore: 2)
BMC Energy     Open Access  
BMC Evolutionary Biology     Open Access   (Followers: 74, SJR: 1.656, CiteScore: 3)
BMC Family Practice     Open Access   (Followers: 16, SJR: 1.137, CiteScore: 2)
BMC Gastroenterology     Open Access   (Followers: 13, SJR: 1.231, CiteScore: 3)
BMC Genetics     Open Access   (Followers: 32, SJR: 1.16, CiteScore: 3)
BMC Genomics     Open Access   (Followers: 92, SJR: 2.11, CiteScore: 4)
BMC Geriatrics     Open Access   (Followers: 19, SJR: 1.257, CiteScore: 3)
BMC Health Services Research     Open Access   (Followers: 20, SJR: 1.151, CiteScore: 2)
BMC Hematology     Open Access   (Followers: 7, SJR: 0.545, CiteScore: 1)
BMC Immunology     Open Access   (Followers: 11, SJR: 0.993, CiteScore: 3)
BMC Infectious Diseases     Open Access   (Followers: 21, SJR: 1.576, CiteScore: 3)
BMC Intl. Health and Human Rights     Open Access   (Followers: 8, SJR: 1.006, CiteScore: 2)
BMC Materials     Open Access   (Followers: 1)
BMC Medical Education     Open Access   (Followers: 50, SJR: 0.765, CiteScore: 2)
BMC Medical Ethics     Open Access   (Followers: 25, SJR: 1.016, CiteScore: 2)
BMC Medical Genetics     Open Access   (Followers: 9, SJR: 1.109, CiteScore: 2)
BMC Medical Genomics     Open Access   (Followers: 5, SJR: 1.688, CiteScore: 3)
BMC Medical Imaging     Open Access   (Followers: 11, SJR: 0.536, CiteScore: 2)
BMC Medical Informatics and Decision Making     Open Access   (Followers: 25, SJR: 0.812, CiteScore: 2)
BMC Medical Physics     Open Access   (Followers: 8)
BMC Medical Research Methodology     Open Access   (Followers: 8, SJR: 2.221, CiteScore: 3)
BMC Medicine     Open Access   (Followers: 15, SJR: 4.219, CiteScore: 7)
BMC Microbiology     Open Access   (Followers: 17, SJR: 1.242, CiteScore: 3)
BMC Molecular and Cell Biology     Open Access   (Followers: 50, SJR: 1.277, CiteScore: 3)
BMC Molecular Biology     Open Access   (Followers: 207, SJR: 1.216, CiteScore: 2)
BMC Musculoskeletal Disorders     Open Access   (Followers: 30, SJR: 0.951, CiteScore: 2)
BMC Nephrology     Open Access   (Followers: 10, SJR: 1.098, CiteScore: 3)
BMC Neurology     Open Access   (Followers: 23, SJR: 1.006, CiteScore: 2)
BMC Neuroscience     Open Access   (Followers: 18, SJR: 1.12, CiteScore: 2)
BMC Nursing     Open Access   (Followers: 31, SJR: 0.766, CiteScore: 2)
BMC Nutrition     Open Access   (Followers: 12)
BMC Obesity     Open Access   (Followers: 9)
BMC Ophthalmology     Open Access   (Followers: 22, SJR: 0.921, CiteScore: 2)
BMC Oral Health     Open Access   (Followers: 7, SJR: 0.867, CiteScore: 2)
BMC Palliative Care     Open Access   (Followers: 39, SJR: 1.105, CiteScore: 2)
BMC Pediatrics     Open Access   (Followers: 21, SJR: 1.278, CiteScore: 2)
BMC Pharmacology     Open Access   (Followers: 3)
BMC Pharmacology & Toxicology     Open Access   (Followers: 8, SJR: 0.785, CiteScore: 2)
BMC Physiology     Open Access   (Followers: 4, SJR: 0.936, CiteScore: 2)
BMC Plant Biology     Open Access   (Followers: 20, SJR: 1.887, CiteScore: 4)
BMC Pregnancy and Childbirth     Open Access   (Followers: 24, SJR: 1.427, CiteScore: 3)
BMC Proceedings     Full-text available via subscription   (Followers: 2, SJR: 0.302, CiteScore: 1)
BMC Psychiatry     Open Access   (Followers: 41, SJR: 1.346, CiteScore: 3)
BMC Psychology     Open Access   (Followers: 22, SJR: 0.817, CiteScore: 2)
BMC Public Health     Open Access   (Followers: 229, SJR: 1.337, CiteScore: 3)
BMC Pulmonary Medicine     Open Access   (Followers: 7, SJR: 1.373, CiteScore: 3)
BMC Research Notes     Open Access   (Followers: 4, SJR: 0.691, CiteScore: 2)
BMC Rheumatology     Open Access   (Followers: 5)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 36, SJR: 0.926, CiteScore: 2)
BMC Structural Biology     Open Access   (Followers: 8, SJR: 1.024, CiteScore: 2)
BMC Surgery     Open Access   (Followers: 10, SJR: 0.693, CiteScore: 2)
BMC Systems Biology     Open Access   (Followers: 16, SJR: 1.109, CiteScore: 2)
BMC Urology     Open Access   (Followers: 14, SJR: 0.853, CiteScore: 2)
BMC Veterinary Research     Open Access   (Followers: 20, SJR: 0.934, CiteScore: 2)
BMC Women's Health     Open Access   (Followers: 16, SJR: 0.931, CiteScore: 2)
BMC Zoology     Open Access   (Followers: 1)
BMJ Evidence-Based Medicine     Hybrid Journal   (Followers: 9)
Borderline Personality Disorder and Emotion Dysregulation     Open Access   (Followers: 10)
Breast Cancer Research     Open Access   (Followers: 22, SJR: 3.026, CiteScore: 6)
Burns & Trauma     Open Access   (Followers: 14)
CABI Agriculture and Bioscience     Open Access   (Followers: 2)
Cancer & Metabolism     Open Access   (Followers: 7)
Cancer Cell Intl.     Open Access   (Followers: 7, SJR: 1.13, CiteScore: 3)
Cancer Communications     Open Access  
Cancer Convergence     Open Access   (Followers: 1)
Cancer Imaging     Open Access   (Followers: 3, SJR: 1.012, CiteScore: 3)
Cancer Nanotechnology     Open Access   (Followers: 2, SJR: 1.168, CiteScore: 4)
Cancers of the Head & Neck     Open Access   (Followers: 3)
Carbon Balance and Management     Open Access   (Followers: 5, SJR: 0.977, CiteScore: 2)
Cardio-Oncology     Open Access  
Cardiovascular Diabetology     Open Access   (Followers: 10, SJR: 2.157, CiteScore: 5)
Cardiovascular Ultrasound     Open Access   (Followers: 6, SJR: 0.812, CiteScore: 2)
Cell Communication and Signaling     Open Access   (Followers: 3, SJR: 2.211, CiteScore: 4)
Cell Division     Open Access   (Followers: 1, SJR: 2.445, CiteScore: 4)
Cellular & Molecular Biology Letters     Hybrid Journal   (Followers: 3)
Cerebellum & Ataxias     Open Access   (Followers: 1)
Chemistry Central J.     Open Access   (Followers: 5, SJR: 0.607, CiteScore: 3)
Child and Adolescent Psychiatry and Mental Health     Open Access   (Followers: 30, SJR: 0.901, CiteScore: 2)
Chinese Medicine     Open Access   (Followers: 2, SJR: 0.57, CiteScore: 2)
Chinese Neurosurgical J.     Open Access  
Chiropractic & Manual Therapies     Open Access   (Followers: 5, SJR: 0.599, CiteScore: 2)
Clinical and Molecular Allergy     Open Access   (Followers: 5, SJR: 0.933, CiteScore: 3)
Clinical Diabetes and Endocrinology     Open Access   (Followers: 23)
Clinical Epigenetics     Open Access   (Followers: 11, SJR: 2.435, CiteScore: 5)
Clinical Hypertension     Open Access   (Followers: 5)
Conflict and Health     Open Access   (Followers: 8, SJR: 1.851, CiteScore: 3)
Contraception and Reproductive Medicine     Open Access   (Followers: 2)
COPD Research and Practice     Open Access   (Followers: 1, SJR: 0.755, CiteScore: 2)
Cost Effectiveness and Resource Allocation     Open Access   (Followers: 5, SJR: 0.888, CiteScore: 2)
Critical Care     Open Access   (Followers: 82, SJR: 2.48, CiteScore: 5)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 13)
Diabetology & Metabolic Syndrome     Open Access   (Followers: 7, SJR: 0.943, CiteScore: 2)
Diagnostic and Prognostic Research     Open Access  
Diagnostic Pathology     Open Access   (Followers: 14, SJR: 0.818, CiteScore: 2)
Disaster and Military Medicine     Open Access   (Followers: 5)
Emerging Themes in Epidemiology     Open Access   (Followers: 14, SJR: 1.003, CiteScore: 2)
Energy, Sustainability and Society     Open Access   (Followers: 18, SJR: 0.607, CiteScore: 2)
Environmental Health     Open Access   (Followers: 15, SJR: 1.662, CiteScore: 4)
Environmental Health and Preventive Medicine     Open Access   (Followers: 4, SJR: 0.5, CiteScore: 1)
Environmental Microbiome     Open Access   (SJR: 0.768, CiteScore: 2)
Epigenetics & Chromatin     Open Access   (Followers: 8, SJR: 3.767, CiteScore: 5)
European J. of Medical Research     Open Access   (Followers: 2, SJR: 0.55, CiteScore: 1)
European Review of Aging and Physical Activity     Open Access   (Followers: 12, SJR: 1.308, CiteScore: 4)
Experimental & Translational Stroke Medicine     Open Access   (Followers: 10, SJR: 0.98, CiteScore: 3)
Experimental Hematology & Oncology     Open Access   (Followers: 6, SJR: 0.842, CiteScore: 2)
ExRNA     Open Access  
Eye and Vision     Open Access   (Followers: 1)
Fertility Research and Practice     Open Access   (Followers: 2)
Fibrogenesis & Tissue Repair     Open Access   (SJR: 1.531, CiteScore: 4)
Fisheries and Aquatic Sciences     Open Access   (Followers: 3, SJR: 0.199, CiteScore: 0)
Fluids and Barriers of the CNS     Open Access   (Followers: 3, SJR: 2.054, CiteScore: 5)
Frontiers in Zoology     Open Access   (Followers: 12, SJR: 1.597, CiteScore: 3)
Genes and Environment     Open Access   (Followers: 1, SJR: 0.516, CiteScore: 1)
Genetics Selection Evolution     Open Access   (Followers: 7, SJR: 1.745, CiteScore: 4)
Genome Biology     Open Access   (Followers: 41)
Genome Medicine     Open Access   (Followers: 7, SJR: 4.537, CiteScore: 7)
Global Health Research and Policy     Open Access   (Followers: 4)
Globalization and Health     Open Access   (Followers: 9, SJR: 1.262, CiteScore: 2)
Gut Pathogens     Full-text available via subscription   (Followers: 6, SJR: 1.066, CiteScore: 3)
Gynecologic Oncology Research and Practice     Open Access   (Followers: 1)
Harm Reduction J.     Open Access   (SJR: 1.445, CiteScore: 3)
Head & Face Medicine     Open Access   (Followers: 1, SJR: 0.62, CiteScore: 2)
Health and Quality of Life Outcomes     Open Access   (Followers: 15, SJR: 1.069, CiteScore: 3)
Health Research Policy and Systems     Open Access   (Followers: 16, SJR: 1.11, CiteScore: 2)
Hereditary Cancer in Clinical Practice     Open Access   (Followers: 2, SJR: 0.848, CiteScore: 2)
Hereditas     Open Access   (Followers: 1, SJR: 0.278, CiteScore: 1)
Human Genomics     Open Access   (Followers: 3, SJR: 1.501, CiteScore: 3)
Human Resources for Health     Open Access   (Followers: 12, SJR: 1.301, CiteScore: 2)
Immunity & Ageing     Open Access   (Followers: 10, SJR: 1.218, CiteScore: 3)
Implementation Science     Open Access   (Followers: 23, SJR: 2.443, CiteScore: 4)
Implementation Science Communications     Open Access   (Followers: 6)
Infectious Agents and Cancer     Open Access   (SJR: 0.855, CiteScore: 2)
Infectious Diseases of Poverty     Open Access   (Followers: 3, SJR: 1.212, CiteScore: 3)
Inflammation and Regeneration     Open Access   (Followers: 2)
Intl. Breastfeeding J.     Open Access   (Followers: 26, SJR: 0.913, CiteScore: 3)
Intl. J. for Equity in Health     Open Access   (Followers: 9, SJR: 1.04, CiteScore: 2)
Intl. J. of Behavioral Nutrition and Physical Activity     Open Access   (Followers: 32, SJR: 2.626, CiteScore: 6)
Intl. J. of Health Geographics     Open Access   (Followers: 9, SJR: 1.385, CiteScore: 3)
Intl. J. of Mental Health Systems     Open Access   (Followers: 7, SJR: 0.721, CiteScore: 2)
Intl. J. of Pediatric Endocrinology     Open Access   (Followers: 12)
Intl. J. of Retina and Vitreous     Open Access   (Followers: 4)
Investigative Genetics     Open Access   (Followers: 1, SJR: 1.809, CiteScore: 3)
Irish Veterinary J.     Open Access   (Followers: 4, SJR: 0.657, CiteScore: 1)
Israel J. of Health Policy Research     Open Access   (SJR: 0.488, CiteScore: 1)
Italian J. of Pediatrics     Open Access   (Followers: 2, SJR: 0.685, CiteScore: 2)
J. of Angiogenesis Research     Open Access   (Followers: 2)

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Journal Cover
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  [308 journals]
  • A recurrent RYR1 mutation associated with early-onset hypotonia and benign
           disease course

    • Abstract: The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
      PubDate: 2021-09-17
       
  • MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid
           angiopathy

    • Abstract: Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.
      PubDate: 2021-09-16
       
  • The intracellular milieu of Parkinson’s disease patient brain cells
           modulates alpha-synuclein protein aggregation

    • Abstract: Recent studies suggest that brain cell type specific intracellular environments may play important roles in the generation of structurally different protein aggregates that define neurodegenerative diseases. Using human induced pluripotent stem cells (hiPSC) and biochemical and vibrational spectroscopy techniques, we studied whether Parkinson’s disease (PD) patient genomes could modulate alpha-synuclein (aSYN) protein aggregates formation. We found increased β-sheets and aggregated aSYN in PD patient hiPSC-derived midbrain cells, compared to controls. Importantly, we discovered that aSYN protein aggregation is modulated by patient brain cells’ intracellular milieus at the primary nucleation phase. Additionally, we found changes in the formation of aSYN fibrils when employing cellular extracts from familial PD compared to idiopathic PD, in a Thioflavin T-based fluorescence assay. The data suggest that changes in cellular milieu induced by patient genomes trigger structural changes of aSYN potentially leading to the formation of strains having different structures, properties and seeding propensities.
      PubDate: 2021-09-16
       
  • Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in
           risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights:
           a retrospective genetic association study

    • Abstract: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer’s pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer’s-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.
      PubDate: 2021-09-15
       
  • Exogenous Aβ seeds induce Aβ depositions in the blood vessels rather
           than the brain parenchyma, independently of Aβ strain-specific
           information

    • Abstract: Little is known about the effects of parenchymal or vascular amyloid β peptide (Aβ) deposition in the brain. We hypothesized that Aβ strain-specific information defines whether Aβ deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aβ plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer’s disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aβ. One year after the injection, the pathological and biochemical features of Aβ in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aβ depositions were observed in the mice that were injected with the human brain homogenate from the less Aβ group. The Aβ and CAA seeding activities, which had significant positive correlations with the Aβ oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aβ group than in the other three groups. These results indicate that exogenous Aβ seeds from different Aβ pathologies induced Aβ deposition in the blood vessels rather than the brain parenchyma without being influenced by Aβ strain-specific information, which might be why CAA is a predominant feature of Aβ pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aβ pathology might occur due to contamination of brain tissues from patients with little Aβ pathology, and the development of inactivation methods for Aβ seeding activity to prevent iatrogenic transmission is urgently required.
      PubDate: 2021-09-10
       
  • Synaptic tau: A pathological or physiological phenomenon'

    • Abstract: In this review, we discuss the synaptic aspects of Tau pathology occurring during Alzheimer’s disease (AD) and how this may relate to memory impairment, a major hallmark of AD. Whilst the clinical diagnosis of AD patients is a loss of working memory and long-term declarative memory, the histological diagnosis is the presence of neurofibrillary tangles of hyperphosphorylated Tau and Amyloid-beta plaques. Tau pathology spreads through synaptically connected neurons to impair synaptic function preceding the formation of neurofibrillary tangles, synaptic loss, axonal retraction and cell death. Alongside synaptic pathology, recent data suggest that Tau has physiological roles in the pre- or post- synaptic compartments. Thus, we have seen a shift in the research focus from Tau as a microtubule-stabilising protein in axons, to Tau as a synaptic protein with roles in accelerating spine formation, dendritic elongation, and in synaptic plasticity coordinating memory pathways. We collate here the myriad of emerging interactions and physiological roles of synaptic Tau, and discuss the current evidence that synaptic Tau contributes to pathology in AD.
      PubDate: 2021-09-09
       
  • Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden
           and neuritic plaque tau pathology in 5XFAD mice

    • Abstract: Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer’s disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2−/− mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/− mice had significantly more plaque-associated microglia than 5XFAD × TREM2−/− mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/− mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/− mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2−/− mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/− and 5XFAD × TREM2−/− mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/− and TREM2−/− mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.
      PubDate: 2021-09-09
       
  • Immune cell deconvolution of bulk DNA methylation data reveals an
           association with methylation class, key somatic alterations, and cell
           state in glial/glioneuronal tumors

    • Abstract: It is recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of immune cell components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data in a large set of newly profiled samples (n = 741) as well as samples from external data sources (n = 3311) of methylation-defined glial and glioneuronal tumors. Using the cell-type proportion data as input, we used dimensionality reduction to visualize sample-wise patterns that emerge from the cell type proportion estimations. In IDH-wildtype glioblastomas (n = 2,072), we identified distinct tumor clusters based on immune cell proportion and demonstrated an association with oncogenic alterations such as EGFR amplification and CDKN2A/B homozygous deletion. We also investigated the immune cluster-specific distribution of four malignant cellular states (AC-like, OPC-like, MES-like and NPC-like) in the IDH-wildtype cohort. We identified two major immune-based subgroups of IDH-mutant gliomas, which largely aligned with 1p/19q co-deletion status. Non-codeleted gliomas showed distinct proportions of a key genomic aberration (CDKN2A/B loss) among immune cell-based groups. We also observed significant positive correlations between monocyte proportion and expression of PD-L1 and PD-L2 (R = 0.54 and 0.68, respectively). Overall, the findings highlight specific roles of the TME in biology and classification of CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic alterations.
      PubDate: 2021-09-08
       
  • Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the
           emerging role of genomic analysis

    • Abstract: Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of ‘oligodendroglioma-like’ appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.
      PubDate: 2021-09-07
       
  • Disease-, region- and cell type specific diversity of α-synuclein carboxy
           terminal truncations in synucleinopathies

    • Abstract: Synucleinopathies, including Parkinson’s disease (PD), Lewy body dementia (LBD), Alzheimer’s disease with amygdala restricted Lewy bodies (AD/ALB), and multiple system atrophy (MSA) comprise a spectrum of neurodegenerative disorders characterized by the presence of distinct pathological α-synuclein (αSyn) inclusions. Experimental and pathological studies support the notion that αSyn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of αSyn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of αSyn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote αSyn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in αSyn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the αSyn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the substantia nigra and amygdala were positive for αSyn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain αSyn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD/ALB, these modifications were only weakly or not detected in amygdala αSyn inclusions. αSyn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved αSyn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the αSyn x-122 neo-epitope but did not display any reactivity for αSyn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal αSyn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases.
      PubDate: 2021-08-28
       
  • Prion strains associated with iatrogenic CJD in French and UK human growth
           hormone recipients

    • Abstract: Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt–Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.
      PubDate: 2021-08-28
       
  • Blood-spinal cord barrier leakage is independent of motor neuron pathology
           in ALS

    • Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. The pattern of lower motor neuron loss along the spinal cord follows the pattern of deposition of phosphorylated TDP-43 aggregates. The blood-spinal cord barrier (BSCB) restricts entry into the spinal cord parenchyma of blood components that can promote motor neuron degeneration, but in ALS there is evidence for barrier breakdown. Here we sought to quantify BSCB breakdown along the spinal cord axis, to determine whether BSCB breakdown displays the same patterning as motor neuron loss and TDP-43 proteinopathy. Cerebrospinal fluid hemoglobin was measured in living ALS patients (n = 87 control, n = 236 ALS) as a potential biomarker of BSCB and blood–brain barrier leakage. Cervical, thoracic, and lumbar post-mortem spinal cord tissue (n = 5 control, n = 13 ALS) were then immunolabelled and semi-automated imaging and analysis performed to quantify hemoglobin leakage, lower motor neuron loss, and phosphorylated TDP-43 inclusion load. Hemoglobin leakage was observed along the whole ALS spinal cord axis and was most severe in the dorsal gray and white matter in the thoracic spinal cord. In contrast, motor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the anterior gray matter of the cervical and lumbar cord. Our data show that leakage of the BSCB occurs during life, but at end-stage disease the regions with most severe BSCB damage are not those where TDP-43 accumulation is most abundant. This suggests BSCB leakage and TDP-43 pathology are independent pathologies in ALS.
      PubDate: 2021-08-26
       
  • Defining tumor-associated vascular heterogeneity in pediatric high-grade
           and diffuse midline gliomas

    • Abstract: The blood–brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.
      PubDate: 2021-08-23
       
  • Importance of extracellular vesicle secretion at the blood–cerebrospinal
           fluid interface in the pathogenesis of Alzheimer’s disease

    • Abstract: Increasing evidence indicates that extracellular vesicles (EVs) play an important role in the pathogenesis of Alzheimer’s disease (AD). We previously reported that the blood–cerebrospinal fluid (CSF) interface, formed by the choroid plexus epithelial (CPE) cells, releases an increased amount of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-mediated EV release in AD pathogenesis. We observed increased EV levels in the CSF of young transgenic APP/PS1 mice which correlated with high amyloid beta (Aβ) CSF levels at this age. The intracerebroventricular (icv) injection of Aβ oligomers (AβO) in wild-type mice revealed a significant increase of EVs in the CSF, signifying that the presence of CSF-AβO is sufficient to induce increased EV secretion. Using in vivo, in vitro and ex vivo approaches, we identified the CP as a major source of the CSF-EVs. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures. Proteome analysis of these EVs revealed the presence of several pro-inflammatory proteins, including the complement protein C3. Strikingly, inhibition of EV production using GW4869 resulted in protection against acute AβO-induced cognitive decline. Further research into the underlying mechanisms of this EV secretion might open up novel therapeutic strategies to impact the pathogenesis and progression of AD.
      PubDate: 2021-08-23
       
  • Deep learning assisted quantitative assessment of histopathological
           markers of Alzheimer’s disease and cerebral amyloid angiopathy

    • Abstract: Traditionally, analysis of neuropathological markers in neurodegenerative diseases has relied on visual assessments of stained sections. Resulting semiquantitative scores often vary between individual raters and research centers, limiting statistical approaches. To overcome these issues, we have developed six deep learning-based models, that identify some of the most characteristic markers of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). The deep learning-based models are trained to differentially detect parenchymal amyloid β (Aβ)-plaques, vascular Aβ-deposition, iron and calcium deposition, reactive astrocytes, microglia, as well as fibrin extravasation. The models were trained on digitized histopathological slides from brains of patients with AD and CAA, using a workflow that allows neuropathology experts to train convolutional neural networks (CNNs) on a cloud-based graphical interface. Validation of all models indicated a very good to excellent performance compared to three independent expert human raters. Furthermore, the Aβ and iron models were consistent with previously acquired semiquantitative scores in the same dataset and allowed the use of more complex statistical approaches. For example, linear mixed effects models could be used to confirm the previously described relationship between leptomeningeal CAA severity and cortical iron accumulation. A similar approach enabled us to explore the association between neuroinflammation and disparate Aβ pathologies. The presented workflow is easy for researchers with pathological expertise to implement and is customizable for additional histopathological markers. The implementation of deep learning-assisted analyses of histopathological slides is likely to promote standardization of the assessment of neuropathological markers across research centers, which will allow specific pathophysiological questions in neurodegenerative disease to be addressed in a harmonized way and on a larger scale.
      PubDate: 2021-08-21
       
  • Microglial transcriptome analysis in the rNLS8 mouse model of TDP-43
           proteinopathy reveals discrete expression profiles associated with
           neurodegenerative progression and recovery

    • Abstract: The microglial reaction is a hallmark of neurodegenerative conditions, and elements thereof may exert differential effects on disease progression, either worsening or ameliorating severity. In amyotrophic lateral sclerosis (ALS), a syndrome characterized by cytoplasmic aggregation of TDP-43 protein and atrophy of motor neurons in the cortex and spinal cord, the transcriptomic signatures of microglia during disease progression are incompletely understood. Here, we performed longitudinal RNAseq analysis of cortical and spinal cord microglia from rNLS8 mice, in which doxycycline-regulatable expression of human TDP-43 (hTDP-43) in the cytoplasm of neurons recapitulates many features of ALS. Transgene suppression in rNLS8 mice leads to functional, anatomical and electrophysiological resolution that is dependent on a microglial reaction that is concurrent with recovery rather than disease onset. We identified basal differences between the gene expression profiles of microglia dependent on localization in spinal cord or cortex. Microglia subjected to chronic hTDP-43 overexpression demonstrated transcriptomic changes in both locations. We noted strong upregulation of Apoe, Axl, Cd63, Clec7a, Csf1, Cst7, Igf1, Itgax, Lgals3, Lilrb4, Lpl and Spp1 during late disease and recovery. Importantly, we identified a distinct suite of differentially expressed genes associated with each phase of disease progression and recovery. Differentially expressed genes were associated with chemotaxis, phagocytosis, inflammation, and production of neuroprotective factors. These data provide new insights into the microglial reaction in TDP-43 proteinopathy. Genes differentially expressed during progression and recovery may provide insight into a unique instance in which the microglial reaction promotes functional recovery after neuronal insult.
      PubDate: 2021-08-19
       
  • Experimental colitis promotes sustained, sex-dependent, T-cell-associated
           neuroinflammation and parkinsonian neuropathology

    • Abstract: Background The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. Methods We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. Results High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. Conclusions This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. Graphical abstract
      PubDate: 2021-08-19
       
  • RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and
           improves memory function after traumatic brain injury

    • Abstract: Traumatic brain injury (TBI) causes acute and subacute tissue damage, but is also associated with chronic inflammation and progressive loss of brain tissue months and years after the initial event. The trigger and the subsequent molecular mechanisms causing chronic brain injury after TBI are not well understood. The aim of the current study was therefore to investigate the hypothesis that necroptosis, a form a programmed cell death mediated by the interaction of Receptor Interacting Protein Kinases (RIPK) 1 and 3, is involved in this process. Neuron-specific RIPK1- or RIPK3-deficient mice and their wild-type littermates were subjected to experimental TBI by controlled cortical impact. Posttraumatic brain damage and functional outcome were assessed longitudinally by repetitive magnetic resonance imaging (MRI) and behavioral tests (beam walk, Barnes maze, and tail suspension), respectively, for up to three months after injury. Thereafter, brains were investigated by immunohistochemistry for the necroptotic marker phosphorylated mixed lineage kinase like protein(pMLKL) and activation of astrocytes and microglia. WT mice showed progressive chronic brain damage in cortex and hippocampus and increased levels of pMLKL after TBI. Chronic brain damage occurred almost exclusively in areas with iron deposits and was significantly reduced in RIPK1- or RIPK3-deficient mice by up to 80%. Neuroprotection was accompanied by a reduction of astrocyte and microglia activation and improved memory function. The data of the current study suggest that progressive chronic brain damage and cognitive decline after TBI depend on the expression of RIPK1/3 in neurons. Hence, inhibition of necroptosis signaling may represent a novel therapeutic target for the prevention of chronic post-traumatic brain damage.
      PubDate: 2021-08-17
       
  • Forebrain Shh overexpression improves cognitive function and locomotor
           hyperactivity in an aneuploid mouse model of Down syndrome and its euploid
           littermates

    • Abstract: Down syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model “Ts65Dn” shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice “Camk2a-tTA;TRE-hShh” and “Pcp2-tTA;TRE-hShh” induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.
      PubDate: 2021-08-16
       
  • The pathogenic role of c-Kit+ mast cells in the spinal motor
           neuron-vascular niche in ALS

    • Abstract: Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.
      PubDate: 2021-08-13
       
 
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