750 results match your criteria Acta neuropathologica communications[Journal]


Neurodegeneration and contralateral α-synuclein induction after intracerebral α-synuclein injections in the anterior olfactory nucleus of a Parkinson's disease A53T mouse model.

Acta Neuropathol Commun 2019 Apr 15;7(1):56. Epub 2019 Apr 15.

Neuroplasticity and Neurodegeneration Laboratory, CRIB, Ciudad Real Medical School, University of Castilla-La Mancha, Camino de Moledores s/n, Ciudad Real, 13071, Spain.

Parkinson's disease is characterized by a proteinopathy that includes aggregates of α-synuclein. A recent hypothesis proposes a prion-like spreading mechanism for this α-synucleinopathy. Early neuropathological deposits occur, among others, in the anterior olfactory nucleus (AON). Read More

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http://dx.doi.org/10.1186/s40478-019-0713-7DOI Listing

Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis.

Acta Neuropathol Commun 2019 Apr 10;7(1):55. Epub 2019 Apr 10.

Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.

Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. Read More

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http://dx.doi.org/10.1186/s40478-019-0712-8DOI Listing
April 2019
5 Reads

The characterization of AD/PART co-pathology in CJD suggests independent pathogenic mechanisms and no cross-seeding between misfolded Aβ and prion proteins.

Acta Neuropathol Commun 2019 Apr 8;7(1):53. Epub 2019 Apr 8.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Current evidence indicating a role of the human prion protein (PrP) in amyloid-beta (Aβ) formation or a synergistic effect between Aβ and prion pathology remains controversial. Conflicting results also concern the frequency of the association between the two protein misfolding disorders and the issue of whether the apolipoprotein E gene (APOE) and the prion protein gene (PRNP), the major modifiers of Aβ- and PrP-related pathologies, also have a pathogenic role in other proteinopathies, including tau neurofibrillary degeneration. Here, we thoroughly characterized the Alzheimer's disease/primary age-related tauopathy (AD/PART) spectrum in a series of 450 cases with definite sporadic or genetic Creutzfeldt-Jakob disease (CJD). Read More

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http://dx.doi.org/10.1186/s40478-019-0706-6DOI Listing
April 2019
1 Read

Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure.

Acta Neuropathol Commun 2019 Apr 8;7(1):54. Epub 2019 Apr 8.

Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM, 87131-0001, USA.

Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1β protein expression. Additionally, the β2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated. Read More

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http://dx.doi.org/10.1186/s40478-019-0701-yDOI Listing
April 2019
3 Reads

Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas.

Acta Neuropathol Commun 2019 Apr 3;7(1):52. Epub 2019 Apr 3.

Shirsat Laboratory, Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India.

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Read More

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http://dx.doi.org/10.1186/s40478-019-0697-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448261PMC

AQP4ex is crucial for the anchoring of AQP4 at the astrocyte end-feet and for neuromyelitis optica antibody binding.

Acta Neuropathol Commun 2019 Apr 1;7(1):51. Epub 2019 Apr 1.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, School of Medicine, University of Bari Aldo Moro, Bari, Italy.

Brain water homeostasis is essential for the appropriate control of neuronal activity. Furthermore, the encasement of the central nervous system (CNS) by a hard structure, greatly limits its tolerance for the volume changes occurring with acute brain edema, which quickly leads to severe damage or death.The recent discovery of the extended isoform of AQP4 (AQP4ex), generated by translational readthrough, revealed a potential new mechanism of water transport regulation and polarization at the blood-brain-barrier level. Read More

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http://dx.doi.org/10.1186/s40478-019-0707-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444679PMC
April 2019
1 Read

Tau and TDP-43 accumulation of the basal nucleus of Meynert in individuals with cerebral lobar infarcts or hemorrhage.

Acta Neuropathol Commun 2019 Mar 28;7(1):49. Epub 2019 Mar 28.

Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

A previous study reported that a massive cerebral infarct in the territory of the middle cerebral artery (MCA) may be associated with development of neurofibrillary tangles (NFTs) in the ipsilateral basal nucleus of Meynert (BNM). We analyzed 19 cases of an MCA territory infarct and 12 with a putaminal hemorrhage (mean age 82.5 years; female/male ratio 8/23; mean time from stroke onset to autopsy 4182 days). Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0700-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437979PMC
March 2019
2 Reads

Transcriptomopathies of pre- and post-symptomatic frontotemporal dementia-like mice with TDP-43 depletion in forebrain neurons.

Acta Neuropathol Commun 2019 Mar 29;7(1):50. Epub 2019 Mar 29.

Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan, Republic of China.

TAR DNA-binding protein (TDP-43) is a ubiquitously expressed nuclear protein, which participates in a number of cellular processes and has been identified as the major pathological factor in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we constructed a conditional TDP-43 mouse with depletion of TDP-43 in the mouse forebrain and find that the mice exhibit a whole spectrum of age-dependent frontotemporal dementia-like behaviour abnormalities including perturbation of social behaviour, development of dementia-like behaviour, changes of activities of daily living, and memory loss at a later stage of life. These variations are accompanied with inflammation, neurodegeneration, and abnormal synaptic plasticity of the mouse CA1 neurons. Read More

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http://dx.doi.org/10.1186/s40478-019-0674-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440020PMC
March 2019
1 Read

Microglia are not required for prion-induced retinal photoreceptor degeneration.

Acta Neuropathol Commun 2019 Mar 25;7(1):48. Epub 2019 Mar 25.

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA.

Degeneration of photoreceptors in the retina is a major cause of blindness in humans. Often retinal degeneration is due to inheritance of mutations in genes important in photoreceptor (PR) function, but can also be induced by other events including retinal trauma, microvascular disease, virus infection or prion infection. The onset of apoptosis and degeneration of PR neurons correlates with invasion of the PR cellular areas by microglia or monocytes, suggesting a causal role for these cells in pathogenesis of PR degenerative disease. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0702-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432762PMC
March 2019
7 Reads

Quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis.

Acta Neuropathol Commun 2019 Mar 18;7(1):45. Epub 2019 Mar 18.

School of Life Sciences, University of Westminster, London, UK.

Over the past two decades a number of studies have demonstrated activity of the retroviral enzyme reverse transcriptase in the serum of patients with sporadic amyotrophic lateral sclerosis (ALS). Known human exogenous retroviruses such as HIV-1 have been eliminated as possible sources of this activity and investigators have therefore considered the possibility that human endogenous retroviruses (HERVs) might be involved. HERV-K (HML-2) is the most recent retroviral candidate to be proposed following the observation of elevated HERV-K expression in cortical and spinal neurons of ALS patients and the demonstration of HERV-K envelope protein neurotoxicity in vitro and in transgenic mice. Read More

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http://dx.doi.org/10.1186/s40478-019-0698-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421708PMC
March 2019
1 Read

Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice.

Acta Neuropathol Commun 2019 Mar 18;7(1):46. Epub 2019 Mar 18.

INSERM UMR1169, 92265, Fontenay-aux-Roses, France.

Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0678-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421685PMC
March 2019
4 Reads

Assembly of transgenic human P301S Tau is necessary for neurodegeneration in murine spinal cord.

Acta Neuropathol Commun 2019 Mar 18;7(1):44. Epub 2019 Mar 18.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.

A pathological pathway leading from soluble monomeric to insoluble filamentous Tau is characteristic of many human neurodegenerative diseases, which also exhibit dysfunction and death of brain cells. However, it is unknown how the assembly of Tau into filaments relates to cell loss. To study this, we first used a mouse line transgenic for full-length human mutant P301S Tau to investigate the temporal relationship between Tau assembly into filaments, assessed using anti-Tau antibody AT100, and motor neuron numbers, in the lumbar spinal cord. Read More

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http://dx.doi.org/10.1186/s40478-019-0695-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421678PMC

Tumor cell-free DNA detection in CSF for primary CNS lymphoma diagnosis.

Acta Neuropathol Commun 2019 Mar 18;7(1):43. Epub 2019 Mar 18.

Laboratoire d'Hématologie- Groupe Hospitalier de la Région de Mulhouse Sud-Alsace, Hôpital E. Muller, 20 avenue de Dr Laennec, 68100, Mulhouse, France.

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http://dx.doi.org/10.1186/s40478-019-0692-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421652PMC

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis.

Acta Neuropathol Commun 2019 Mar 15;7(1):42. Epub 2019 Mar 15.

Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Read More

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http://dx.doi.org/10.1186/s40478-019-0689-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419470PMC
March 2019
1 Read

Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration.

Acta Neuropathol Commun 2019 Mar 14;7(1):41. Epub 2019 Mar 14.

Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue N.E, Grand Rapids, MI, 49503, USA.

Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson's disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. Read More

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http://dx.doi.org/10.1186/s40478-019-0696-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419482PMC
March 2019
1 Read

Postnatal development and maturation of layer 1 in the lateral prefrontal cortex and its disruption in autism.

Acta Neuropathol Commun 2019 Mar 13;7(1):40. Epub 2019 Mar 13.

Human Systems Neuroscience Laboratory, Boston University, 635 Commonwealth Ave., Room 401D, Boston, MA, 02215, USA.

Autism is a neurodevelopmental connectivity disorder characterized by cortical network disorganization and imbalance in excitation/inhibition. However, little is known about the development of autism pathology and the disruption of laminar-specific excitatory and inhibitory cortical circuits. To begin to address these issues, we examined layer 1 of the lateral prefrontal cortex (LPFC), an area with prolonged development and maturation that is affected in autism. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0684-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417186PMC
March 2019
5 Reads

HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis.

Acta Neuropathol Commun 2019 Mar 13;7(1):39. Epub 2019 Mar 13.

Department of Clinical Genetics, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.

Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington's disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson's disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. Read More

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http://dx.doi.org/10.1186/s40478-019-0694-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416930PMC
March 2019
1 Read

Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis.

Acta Neuropathol Commun 2019 Mar 11;7(1):38. Epub 2019 Mar 11.

Institut NeuroMyogène, Equipe Synaptopathies et Autoanticorps (SynatAc), INSERM U1217/UMR CRS 5310, Lyon, France.

Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. Read More

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http://dx.doi.org/10.1186/s40478-019-0693-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410529PMC
March 2019
2 Reads

Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue.

Acta Neuropathol Commun 2019 Mar 11;7(1):37. Epub 2019 Mar 11.

Department of Neurology, Massachusetts General Hospital, WACC, Suite 715, 15th Parkman St., Boston, MA, 02114, USA.

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0686-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410510PMC
March 2019
8 Reads

Tau exhibits unique seeding properties in globular glial tauopathy.

Acta Neuropathol Commun 2019 Mar 7;7(1):36. Epub 2019 Mar 7.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0691-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404306PMC
March 2019
4 Reads

The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity.

Acta Neuropathol Commun 2019 Mar 6;7(1):35. Epub 2019 Mar 6.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RX, UK.

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by "tethering proteins" that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether. Read More

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http://dx.doi.org/10.1186/s40478-019-0688-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402140PMC
March 2019
1 Read

Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau).

Acta Neuropathol Commun 2019 Mar 4;7(1):34. Epub 2019 Mar 4.

Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce St. 3 Maloney, Philadelphia, PA, 19104, USA.

Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of corticobasal degeneration (CBD; n = 49), progressive supranuclear palsy (PSP; n = 109), and Pick's disease (PiD; n = 22). Nearly two-thirds of patients (n = 115 of 180, 63. Read More

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http://dx.doi.org/10.1186/s40478-019-0687-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399892PMC
March 2019
2 Reads

A simplified approach using Taqman low-density array for medulloblastoma subgrouping.

Acta Neuropathol Commun 2019 Mar 4;7(1):33. Epub 2019 Mar 4.

Department of Pediatrics Ribeirão Preto Medical School, Hospital das Clínicas, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil.

Next-generation sequencing platforms are routinely used for molecular assignment due to their high impact for risk stratification and prognosis in medulloblastomas. Yet, low and middle-income countries still lack an accurate cost-effective platform to perform this allocation. TaqMan Low Density array (TLDA) assay was performed using a set of 20 genes in 92 medulloblastoma samples. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0681-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398239PMC
March 2019
7 Reads

C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner.

Acta Neuropathol Commun 2019 Mar 4;7(1):32. Epub 2019 Mar 4.

Center for Craniofacial Molecular Biology, University of Southern California (USC), Los Angeles, CA, 90033, USA.

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http://dx.doi.org/10.1186/s40478-019-0685-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398253PMC

The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Acta Neuropathol Commun 2019 Mar 1;7(1):31. Epub 2019 Mar 1.

University of Lille, CNRS, UMR8576, 59000, Lille, France.

Insights into tau molecular structures have advanced significantly in recent years. This field has been the subject of recent breakthroughs, including the first cryo-electron microscopy structures of tau filaments from Alzheimer's and Pick's disease inclusions, as well as the structure of the repeat regions of tau bound to microtubules. Tau structure covers various species as the tau protein itself takes many forms. Read More

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http://dx.doi.org/10.1186/s40478-019-0682-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397507PMC
March 2019
1 Read

Altered myogenesis and premature senescence underlie human TRIM32-related myopathy.

Acta Neuropathol Commun 2019 Mar 1;7(1):30. Epub 2019 Mar 1.

Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c. Read More

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http://dx.doi.org/10.1186/s40478-019-0683-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396567PMC

Pathogenic tau modifications occur in axons before the somatodendritic compartment in mossy fiber and Schaffer collateral pathways.

Acta Neuropathol Commun 2019 Feb 28;7(1):29. Epub 2019 Feb 28.

Department of Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, 400 Monroe Ave NW, Grand Rapids, MI, 49053, USA.

The deposition of tau pathology in Alzheimer's disease (AD) may occur first in axons of neurons and then progress back into the cell bodies to form neurofibrillary tangles, however, studies have not directly analyzed this relationship in relatively discrete circuits within the human hippocampus. In the early phases of tau deposition, both AT8 phosphorylation and exposure of the amino terminus of tau occurs in tauopathies, and these modifications are linked to mechanisms of synaptic and axonal dysfunction. Here, we examined the localization of these tau pathologies in well-characterized post-mortem human tissue samples from the hippocampus of 44 cases ranging between non-demented and mild cognitively impaired to capture a time at which intrahippocampal pathways show a range in the extent of tau deposition. Read More

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http://dx.doi.org/10.1186/s40478-019-0675-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394076PMC
February 2019

Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy.

Acta Neuropathol Commun 2019 Feb 26;7(1):26. Epub 2019 Feb 26.

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Read More

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http://dx.doi.org/10.1186/s40478-019-0680-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390363PMC
February 2019
2 Reads

LRRK2 inhibition does not impart protection from α-synuclein pathology and neuron death in non-transgenic mice.

Acta Neuropathol Commun 2019 Feb 26;7(1):28. Epub 2019 Feb 26.

Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3600 Spruce St, 3rd Floor Maloney, Philadelphia, PA, 19104-4283, USA.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the most common causes of familial Parkinson's disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. Read More

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http://dx.doi.org/10.1186/s40478-019-0679-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391792PMC
February 2019
1 Read

Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology.

Acta Neuropathol Commun 2019 Feb 26;7(1):27. Epub 2019 Feb 26.

Department of Neurological Surgery, University of California, Davis, Davis, CA, USA.

The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Read More

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http://dx.doi.org/10.1186/s40478-019-0677-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390634PMC
February 2019

Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer's disease.

Acta Neuropathol Commun 2019 Feb 22;7(1):25. Epub 2019 Feb 22.

School of Biological Sciences and Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK.

The synaptic changes underlying the onset of cognitive impairment in Alzheimer's disease (AD) are poorly understood. In contrast to the well documented inhibition of long-term potentiation (LTP) in CA3-CA1 synapses by acute Aβ application in adult neurons from rodents, young amyloid precursor protein (APP) transgenic mouse models often, surprisingly, show normal LTP. This suggests that there may be important differences between mature-onset and developmental-onset APP expression/ Aβ accumulation and the ensuing synaptic and behavioural phenotype. Read More

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http://dx.doi.org/10.1186/s40478-019-0670-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387506PMC
February 2019
1 Read

Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre.

Acta Neuropathol Commun 2019 Feb 20;7(1):24. Epub 2019 Feb 20.

Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, WC1N 3BG, UK.

The introduction of the classification of brain tumours based on their DNA methylation profile has significantly changed the diagnostic approach for cases with ambiguous histology, non-informative or contradictory molecular profiles or for entities where methylation profiling provides useful information for patient risk stratification, for example in medulloblastoma and ependymoma. We present our experience that combines a conventional molecular diagnostic approach with the complementary use of a DNA methylation-based classification tool, for adult brain tumours originating from local as well as national referrals. We report the frequency of IDH mutations in a large cohort of nearly 1550 patients, EGFR amplifications in almost 1900 IDH-wildtype glioblastomas, and histone mutations in 70 adult gliomas. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0668-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381711PMC
February 2019
3 Reads

Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke.

Acta Neuropathol Commun 2019 Feb 18;7(1):23. Epub 2019 Feb 18.

Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 240 W Green Street, Athens, GA, 30602, USA.

At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived laminin-α5 is involved in vascular integrity regulation, however, remains unknown. Read More

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http://dx.doi.org/10.1186/s40478-019-0676-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378751PMC
February 2019

A walk through tau therapeutic strategies.

Acta Neuropathol Commun 2019 Feb 15;7(1):22. Epub 2019 Feb 15.

AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, 811 02, Bratislava, Slovakia.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0664-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376692PMC
February 2019
6 Reads

SET SUMOylation promotes its cytoplasmic retention and induces tau pathology and cognitive impairments.

Acta Neuropathol Commun 2019 Feb 15;7(1):21. Epub 2019 Feb 15.

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

PP2A is a major regulator of tau phosphorylation, which is principally regulated by an endogenous nuclear protein inhibitor 2 of PP2A (I), also named SET. However, how SET is post-translationally regulated and translocates from the nucleus to the cytoplasm remain incompletely understood. Here we show SET is SUMOylated at K68 residue that induces its cytoplasmic retention, resulting in Alzheimer disease (AD) like tau pathology and cognitive defects. Read More

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http://dx.doi.org/10.1186/s40478-019-0663-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376727PMC
February 2019
4 Reads

Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma.

Acta Neuropathol Commun 2019 Feb 14;7(1):20. Epub 2019 Feb 14.

Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. Read More

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http://dx.doi.org/10.1186/s40478-019-0665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376799PMC
February 2019

Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation.

Acta Neuropathol Commun 2019 Feb 12;7(1):19. Epub 2019 Feb 12.

Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

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http://dx.doi.org/10.1186/s40478-019-0672-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371429PMC
February 2019
1 Read

Heterogeneous nuclear ribonucleoproteins R and Q accumulate in pathological inclusions in FTLD-FUS.

Acta Neuropathol Commun 2019 Feb 12;7(1):18. Epub 2019 Feb 12.

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.

Frontotemporal lobar degeneration (FTLD) is pathologically subdivided based on the presence of particular pathological proteins that are identified in inclusion bodies observed post-mortem. The FTLD-FUS subgroup is defined by the presence of the fused in sarcoma protein (FUS) in pathological inclusions. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) protein and a member of the FET (FUS, EWS, TAF15) protein family. Read More

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http://dx.doi.org/10.1186/s40478-019-0673-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371513PMC
February 2019

Endothelial edema precedes blood-brain barrier breakdown in early time points after experimental focal cerebral ischemia.

Acta Neuropathol Commun 2019 Feb 11;7(1):17. Epub 2019 Feb 11.

Department of Neurology, University Hospital Leipzig, Liebigstr. 20, Leipzig, Germany.

In the setting of stroke, ischemia-related blood-brain barrier (BBB) dysfunction aggravates the cerebral edema, which critically impacts on the clinical outcome. Further, an impaired vascular integrity is associated with the risk of intracranial bleeding, especially after therapeutic recanalization. Therefore, the present study was aimed to investigate early vascular alterations from 30 min to 4 h after experimental middle cerebral artery occlusion (MCAO) in mice. Read More

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http://dx.doi.org/10.1186/s40478-019-0671-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369548PMC
February 2019
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White matter capillaries in vascular and neurodegenerative dementias.

Acta Neuropathol Commun 2019 Feb 7;7(1):16. Epub 2019 Feb 7.

Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.

Previous studies suggest white matter (WM) integrity is vulnerable to chronic hypoperfusion during brain ageing. We assessed ~ 0.7 million capillary profiles in the frontal lobe WM across several dementias comprising Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease with dementia, vascular dementia, mixed dementias, post-stroke dementia as well as post-stroke no dementia and similar age ageing and young controls without significant brain pathology. Read More

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http://dx.doi.org/10.1186/s40478-019-0666-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366070PMC
February 2019
4 Reads

EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke.

Acta Neuropathol Commun 2019 Feb 5;7(1):15. Epub 2019 Feb 5.

Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-induced neurotoxicity mediated via NMDAR, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2, a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Read More

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http://dx.doi.org/10.1186/s40478-019-0669-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362601PMC
February 2019
4 Reads

Microglia pre-activation and neurodegeneration precipitate neuroinflammation without exacerbating tissue injury in experimental autoimmune encephalomyelitis.

Acta Neuropathol Commun 2019 Jan 31;7(1):14. Epub 2019 Jan 31.

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.

Human inflammatory or neurodegenerative diseases, such as progressive multiple sclerosis (MS), occur on a background of age-related microglia activation and iron accumulation as well as pre-existing neurodegeneration. Most experimental models for CNS diseases, however, are induced in rodents, which are naturally characterized by a homeostatic microglia phenotype, low cellular iron load and absence of neurodegeneration. Here, we show that naïve LEWzizi rats - Lewis rats with a zitter rat background - show a spontaneous phenotype partly mimicking the changes seen in human aging and particularly in the normal-appearing white and grey matter of patients with progressive MS. Read More

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http://dx.doi.org/10.1186/s40478-019-0667-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357376PMC
January 2019

The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease.

Acta Neuropathol Commun 2019 Jan 31;7(1):13. Epub 2019 Jan 31.

Foundation Eclosion, CH-1228, Plan-les-Ouates, Switzerland.

The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-β peptides (Aβ) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aβ production and deposition into senile plaques. Read More

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http://dx.doi.org/10.1186/s40478-019-0660-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354426PMC
January 2019
3 Reads

Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy.

Acta Neuropathol Commun 2019 Jan 28;7(1):12. Epub 2019 Jan 28.

Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. Read More

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http://dx.doi.org/10.1186/s40478-019-0662-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348632PMC
January 2019
1 Read

Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity.

Acta Neuropathol Commun 2019 Jan 24;7(1):11. Epub 2019 Jan 24.

Department of Molecular Medicine, MEM-151, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.

Early in the development of multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), vascular integrity is compromised. This is accompanied by a marked vascular remodeling response, though it is currently unclear whether this is an adaptive vascular repair mechanism or is part of the pathogenic process. In light of the well-described angiogenic role for the α5β1 integrin, the goal of this study was to evaluate how genetic deletion of endothelial α5 integrin (α5-EC-KO mice) impacts vascular remodeling and repair following vascular disruption during EAE pathogenesis, and how this subsequently influences clinical progression and inflammatory demyelination. Read More

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http://dx.doi.org/10.1186/s40478-019-0659-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346510PMC
January 2019
3 Reads

Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant.

Acta Neuropathol Commun 2019 Jan 23;7(1):10. Epub 2019 Jan 23.

Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, Tau-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. Read More

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http://dx.doi.org/10.1186/s40478-019-0661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345061PMC
January 2019
2 Reads

Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth.

Acta Neuropathol Commun 2019 Jan 18;7(1). Epub 2019 Jan 18.

Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.

The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. Read More

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http://dx.doi.org/10.1186/s40478-019-0657-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337872PMC
January 2019
10 Reads

Regulation of dopamine neurotransmission from serotonergic neurons by ectopic expression of the dopamine D2 autoreceptor blocks levodopa-induced dyskinesia.

Acta Neuropathol Commun 2019 Jan 15;7(1). Epub 2019 Jan 15.

Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.

Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson's disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this "false neurotransmission" phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Read More

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http://dx.doi.org/10.1186/s40478-018-0653-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332643PMC
January 2019

ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles.

Acta Neuropathol Commun 2019 Jan 14;7(1). Epub 2019 Jan 14.

School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK.

Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). Mutant FUS is known to confer cytoplasmic gain of function but its effects in the nucleus are less understood. FUS is an essential component of paraspeckles, subnuclear bodies assembled on a lncRNA NEAT1. Read More

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https://actaneurocomms.biomedcentral.com/articles/10.1186/s4
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http://dx.doi.org/10.1186/s40478-019-0658-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330737PMC
January 2019
9 Reads