8,223 results match your criteria Acta neuropathologica[Journal]


Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models.

Acta Neuropathol 2019 Apr 22. Epub 2019 Apr 22.

Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece.

Multiple system atrophy (MSA) is characterized by the presence of distinctive glial cytoplasmic inclusions (GCIs) within oligodendrocytes that contain the neuronal protein alpha-synuclein (aSyn) and the oligodendroglia-specific phosphoprotein TPPP/p25α. However, the role of oligodendroglial aSyn and p25α in the formation of aSyn-rich GCIs remains unclear. To address this conundrum, we have applied human aSyn (haSyn) pre-formed fibrils (PFFs) to rat wild-type (WT)-, haSyn-, or p25α-overexpressing oligodendroglial cells and to primary differentiated oligodendrocytes derived from WT, knockout (KO)-aSyn, and PLP-haSyn-transgenic mice. Read More

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http://dx.doi.org/10.1007/s00401-019-02014-yDOI Listing

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling.

Acta Neuropathol 2019 Apr 22. Epub 2019 Apr 22.

Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127; CNRS, UMR 7225; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UM-75, Paris, France.

Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. Read More

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http://dx.doi.org/10.1007/s00401-019-02011-1DOI Listing

Correction to: The origin, fate, and contribution of macrophages to spinal cord injury pathology.

Acta Neuropathol 2019 May;137(5):799-800

Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, 33136, USA.

The original version of the article contains a labeling error in Fig. 2. The boxed molecular description of pro-inflammatory and anti-inflammatory macrophages were switched. Read More

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http://dx.doi.org/10.1007/s00401-019-02016-wDOI Listing

Selective vulnerability in α-synucleinopathies.

Acta Neuropathol 2019 Apr 20. Epub 2019 Apr 20.

Department of Movement and Clinical Neurosciences, UCL Queen Square Institute of Neurology, University College London, Rowland Hill Street, London, NW3 2PF, UK.

Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. Read More

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http://link.springer.com/10.1007/s00401-019-02010-2
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http://dx.doi.org/10.1007/s00401-019-02010-2DOI Listing
April 2019
1 Read

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease.

Acta Neuropathol 2019 Apr 20. Epub 2019 Apr 20.

Department of Experimental Medical Science, Experimental Neuroinflammation Laboratory, Lund University, 221 84, Lund, Sweden.

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Read More

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http://dx.doi.org/10.1007/s00401-019-02013-zDOI Listing

Detection of AD-specific four repeat tau with deamidated asparagine residue 279-specific fraction purified from 4R tau polyclonal antibody.

Acta Neuropathol 2019 Apr 20. Epub 2019 Apr 20.

Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

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http://dx.doi.org/10.1007/s00401-019-02012-0DOI Listing

The new genetic landscape of Alzheimer's disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

Acta Neuropathol 2019 Apr 13. Epub 2019 Apr 13.

Unité INSERM 1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Institut Pasteur de Lille, University of Lille, U1167-Excellence Laboratory LabEx DISTALZ, BP 245, 1, rue du professeur Calmette, 59019, Lille Cedex, France.

A strong genetic predisposition (60-80% of attributable risk) is present in Alzheimer's disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. Read More

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http://dx.doi.org/10.1007/s00401-019-02004-0DOI Listing
April 2019
1 Read

An update on the central nervous system manifestations of tuberous sclerosis complex.

Acta Neuropathol 2019 Apr 11. Epub 2019 Apr 11.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

The autosomal dominant disorder tuberous sclerosis complex (TSC) is characterized by an array of manifestations both within and outside of the central nervous system (CNS), including hamartomas and other malformations. TSC is caused by mutations in the TSC1 or TSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Study of TSC has shed light on the critical role of the mTOR pathway in neurodevelopment. Read More

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http://link.springer.com/10.1007/s00401-019-02003-1
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http://dx.doi.org/10.1007/s00401-019-02003-1DOI Listing
April 2019
5 Reads

Neurotoxicity of polychlorinated biphenyls and related organohalogens.

Acta Neuropathol 2019 Apr 11. Epub 2019 Apr 11.

Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, CA, USA.

Halogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many "legacy" compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcomes have also been noted. Read More

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http://dx.doi.org/10.1007/s00401-019-01978-1DOI Listing
April 2019
1 Read

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes.

Acta Neuropathol 2019 Apr 11. Epub 2019 Apr 11.

Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. Read More

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http://dx.doi.org/10.1007/s00401-019-02007-xDOI Listing

Neuroinflammation, the thread connecting neurological disease : Cluster: "Neuroinflammatory mechanisms in neurodegenerative disorders".

Acta Neuropathol 2019 May 9;137(5):689-691. Epub 2019 Apr 9.

The Miami Project To Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

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http://dx.doi.org/10.1007/s00401-019-02009-9DOI Listing

An update on the central nervous system manifestations of neurofibromatosis type 1.

Acta Neuropathol 2019 Apr 8. Epub 2019 Apr 8.

Department of Pathology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD, 21231, USA.

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder that presents with variable phenotypes as a result of mutations in the neurofibromatosis type 1 (NF1) gene and subsequently, abnormal function of the protein product, neurofibromin. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic disease. The mechanisms underlying the varied manifestations of NF1 are incompletely understood, but the loss of functional neurofibromin, resulting in sustained activation of the oncoprotein RAS, is responsible for tumorigenesis throughout the body, including the CNS. Read More

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http://dx.doi.org/10.1007/s00401-019-02002-2DOI Listing
April 2019
1 Read

Severe bornavirus-encephalitis presenting as Guillain-Barré-syndrome.

Acta Neuropathol 2019 Apr 5. Epub 2019 Apr 5.

Institute of Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Schlossgarten 4, 91054, Erlangen, Germany.

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http://dx.doi.org/10.1007/s00401-019-02005-zDOI Listing

An update on the central nervous system manifestations of DICER1 syndrome.

Acta Neuropathol 2019 Apr 5. Epub 2019 Apr 5.

Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Bader 104, Boston, MA, 02115, USA.

DICER1 syndrome is a rare tumor predisposition syndrome with manifestations that predominantly affect children and young adults. The syndrome is typically caused by heterozygous germline loss-of-function DICER1 alterations accompanied on the other allele by somatic missense mutations occurring at one of a few mutation hotspots within the sequence encoding the RNase IIIb domain. DICER1 encodes a member of the microRNA biogenesis machinery. Read More

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http://dx.doi.org/10.1007/s00401-019-01997-yDOI Listing
April 2019
2 Reads

Evaluation of CD33 as a genetic risk factor for Alzheimer's disease.

Acta Neuropathol 2019 Apr 4. Epub 2019 Apr 4.

Department of Biostatistics and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

In 2011, genome-wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer's disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer's disease. Read More

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http://dx.doi.org/10.1007/s00401-019-02000-4DOI Listing
April 2019
2 Reads

ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD.

Acta Neuropathol 2019 Apr 3. Epub 2019 Apr 3.

Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.

The hexanucleotide repeat expansion GGGGCC (GC) in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. Read More

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http://dx.doi.org/10.1007/s00401-019-01999-wDOI Listing

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Acta Neuropathol 2019 Apr 1. Epub 2019 Apr 1.

Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany.

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. Read More

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http://dx.doi.org/10.1007/s00401-019-01998-xDOI Listing
April 2019
3 Reads

The origin, fate, and contribution of macrophages to spinal cord injury pathology.

Acta Neuropathol 2019 May 30;137(5):785-797. Epub 2019 Mar 30.

Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, 33136, USA.

Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. Read More

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http://dx.doi.org/10.1007/s00401-019-01992-3DOI Listing
May 2019
1 Read

LRRK2 modifies α-syn pathology and spread in mouse models and human neurons.

Acta Neuropathol 2019 Mar 29. Epub 2019 Mar 29.

Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA, 94305-5120, USA.

Progressive aggregation of the protein alpha-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson's disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of α-syn transmission and aggregation as potential targets to slow down disease progression. Read More

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http://dx.doi.org/10.1007/s00401-019-01995-0DOI Listing
March 2019
2 Reads

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus-Merzbacher disease.

Acta Neuropathol 2019 Mar 27. Epub 2019 Mar 27.

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.

Pelizaeus-Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood-brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not lead to a major advancement of hypomyelination, potentially because the intact blood-brain barrier precludes its entry into the CNS. Read More

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http://dx.doi.org/10.1007/s00401-019-01985-2DOI Listing

An ALS case with 38 (G4C2)-repeats in the C9orf72 gene shows TDP-43 and sparse dipeptide repeat protein pathology.

Acta Neuropathol 2019 May 27;137(5):855-858. Epub 2019 Mar 27.

Department of Neurosciences, Laboratory for Neuropathology, KU Leuven, Leuven Brain Institute (LBI), Leuven, Belgium.

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http://dx.doi.org/10.1007/s00401-019-01996-zDOI Listing
May 2019
1 Read
10.762 Impact Factor

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data.

Acta Neuropathol 2019 Mar 25. Epub 2019 Mar 25.

Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, 76000, Rouen, France.

Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2, SORL1, and ABCA7. SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). Read More

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http://link.springer.com/10.1007/s00401-019-01991-4
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http://dx.doi.org/10.1007/s00401-019-01991-4DOI Listing
March 2019
3 Reads

The role of ABCA7 in Alzheimer's disease: evidence from genomics, transcriptomics and methylomics.

Acta Neuropathol 2019 Mar 22. Epub 2019 Mar 22.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, CDE, Universiteitsplein 1, 2610, Antwerp, Belgium.

Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7, with a focus on AD-related human -omics studies (e. Read More

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http://dx.doi.org/10.1007/s00401-019-01994-1DOI Listing

ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response.

Acta Neuropathol 2019 Mar 14. Epub 2019 Mar 14.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10 mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Read More

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http://dx.doi.org/10.1007/s00401-019-01989-yDOI Listing
March 2019
3 Reads

Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity.

Acta Neuropathol 2019 Mar 15. Epub 2019 Mar 15.

Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave, E516, Cleveland, OH, 44106-4970, USA.

Both α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that αSyn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which αSyn and mitochondrial proteins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Read More

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http://dx.doi.org/10.1007/s00401-019-01993-2DOI Listing
March 2019
3 Reads
10.762 Impact Factor

Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10 mouse.

Acta Neuropathol 2019 Mar 14. Epub 2019 Mar 14.

Inserm U1081, CNRS UMR7284, IRCAN, CHU de Nice, Medicine School, Université Côte d'Azur, 28 av de Valombrose, 06107, Nice Cedex 2, France.

Recently, we provided genetic basis showing that mitochondrial dysfunction can trigger motor neuron degeneration, through identification of CHCHD10 encoding a mitochondrial protein. We reported patients, carrying the p.Ser59Leu heterozygous mutation in CHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Read More

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http://link.springer.com/10.1007/s00401-019-01988-z
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http://dx.doi.org/10.1007/s00401-019-01988-zDOI Listing
March 2019
14 Reads

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Acta Neuropathol 2019 Mar 14. Epub 2019 Mar 14.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. Read More

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http://dx.doi.org/10.1007/s00401-019-01976-3DOI Listing
March 2019
2 Reads
10.762 Impact Factor

The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension.

Acta Neuropathol 2019 Mar 12. Epub 2019 Mar 12.

Department of Pharmacology and Clinical Neuroscience, Umeå University, 90187, Umeå, Sweden.

Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Read More

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http://dx.doi.org/10.1007/s00401-019-01986-1DOI Listing
March 2019
1 Read

cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF mutation.

Acta Neuropathol 2019 Apr 8;137(4):683-687. Epub 2019 Mar 8.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

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http://dx.doi.org/10.1007/s00401-019-01987-0DOI Listing

SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation.

Acta Neuropathol 2019 Apr 8;137(4):675-678. Epub 2019 Mar 8.

Pediatric Oncology Department, SIREDO Oncology Centre (Care, Innovation, Research in Pediatric, Adolescent and Young Adults Oncology), Institut Curie, 26, rue d'Ulm, 75248, Paris Cedex 05, France.

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http://dx.doi.org/10.1007/s00401-019-01983-4DOI Listing
April 2019
2 Reads
10.762 Impact Factor

The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis.

Acta Neuropathol 2019 May 7;137(5):757-783. Epub 2019 Mar 7.

The Miami Project To Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Neuroinflammation is the coordinated response of the central nervous system (CNS) to threats to its integrity posed by a variety of conditions, including autoimmunity, pathogens and trauma. Activated astrocytes, in concert with other cellular elements of the CNS and immune system, are important players in the modulation of the neuroinflammatory response. During neurological disease, they produce and respond to cellular signals that often lead to dichotomous processes, which can promote further damage or contribute to repair. Read More

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http://link.springer.com/10.1007/s00401-019-01980-7
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http://dx.doi.org/10.1007/s00401-019-01980-7DOI Listing
May 2019
6 Reads

Mission not yet completed: on the ups and downs of being the editor of ANP.

Authors:
Werner Paulus

Acta Neuropathol 2019 Apr 5;137(4):531-534. Epub 2019 Mar 5.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Munster, Germany.

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http://dx.doi.org/10.1007/s00401-019-01984-3DOI Listing

TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma.

Acta Neuropathol 2019 Apr 4;137(4):657-673. Epub 2019 Mar 4.

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The TCF4 gene encodes for the basic helix-loop-helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Read More

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http://dx.doi.org/10.1007/s00401-019-01982-5DOI Listing
April 2019
1 Read

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) disclose similar epigenetic signatures but different transcriptional profiles.

Acta Neuropathol 2019 Mar 2. Epub 2019 Mar 2.

Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Read More

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http://dx.doi.org/10.1007/s00401-019-01981-6DOI Listing
March 2019
14 Reads

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains.

Acta Neuropathol 2019 Feb 27. Epub 2019 Feb 27.

Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. Read More

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http://link.springer.com/10.1007/s00401-019-01979-0
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http://dx.doi.org/10.1007/s00401-019-01979-0DOI Listing
February 2019
8 Reads

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology.

Acta Neuropathol 2019 May 25;137(5):825-836. Epub 2019 Feb 25.

Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA.

Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson's disease (PD). It is hypothesized that α-synuclein pathology spreads by a "prion-like" mechanism (i.e. Read More

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http://link.springer.com/10.1007/s00401-019-01974-5
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http://dx.doi.org/10.1007/s00401-019-01974-5DOI Listing
May 2019
6 Reads

α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

Acta Neuropathol 2019 Feb 23. Epub 2019 Feb 23.

Department of Neuroscience, Center for Translational Research in Neurodegenerative Diseases and McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.

α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. Read More

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http://dx.doi.org/10.1007/s00401-019-01977-2DOI Listing
February 2019
1 Read

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms.

Acta Neuropathol 2019 Feb 20. Epub 2019 Feb 20.

Centre de Recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC, G1V 4G2, Canada.

In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington's disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. Read More

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http://dx.doi.org/10.1007/s00401-019-01973-6DOI Listing
February 2019
1 Read

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo.

Acta Neuropathol 2019 Apr 15;137(4):637-655. Epub 2019 Feb 15.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Read More

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http://dx.doi.org/10.1007/s00401-019-01975-4DOI Listing
April 2019
2 Reads
10.762 Impact Factor

Tau drives translational selectivity by interacting with ribosomal proteins.

Acta Neuropathol 2019 Apr 13;137(4):571-583. Epub 2019 Feb 13.

Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, BOX 100159, Gainesville, FL, 32610, USA.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. Read More

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http://dx.doi.org/10.1007/s00401-019-01970-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426815PMC
April 2019
9 Reads

Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA.

Acta Neuropathol 2019 May 13;137(5):837-846. Epub 2019 Feb 13.

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1-PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Read More

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http://dx.doi.org/10.1007/s00401-019-01969-2DOI Listing
May 2019
7 Reads

Translational control in brain pathologies: biological significance and therapeutic opportunities.

Acta Neuropathol 2019 Apr 9;137(4):535-555. Epub 2019 Feb 9.

Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.

Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Read More

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http://dx.doi.org/10.1007/s00401-019-01971-8DOI Listing
April 2019
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Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Authors:
Cyril Pottier Yingxue Ren Ralph B Perkerson Matt Baker Gregory D Jenkins Marka van Blitterswijk Mariely DeJesus-Hernandez Jeroen G J van Rooij Melissa E Murray Elizabeth Christopher Shannon K McDonnell Zachary Fogarty Anthony Batzler Shulan Tian Cristina T Vicente Billie Matchett Anna M Karydas Ging-Yuek Robin Hsiung Harro Seelaar Merel O Mol Elizabeth C Finger Caroline Graff Linn Öijerstedt Manuela Neumann Peter Heutink Matthis Synofzik Carlo Wilke Johannes Prudlo Patrizia Rizzu Javier Simon-Sanchez Dieter Edbauer Sigrun Roeber Janine Diehl-Schmid Bret M Evers Andrew King M Marsel Mesulam Sandra Weintraub Changiz Geula Kevin F Bieniek Leonard Petrucelli Geoffrey L Ahern Eric M Reiman Bryan K Woodruff Richard J Caselli Edward D Huey Martin R Farlow Jordan Grafman Simon Mead Lea T Grinberg Salvatore Spina Murray Grossman David J Irwin Edward B Lee EunRan Suh Julie Snowden David Mann Nilufer Ertekin-Taner Ryan J Uitti Zbigniew K Wszolek Keith A Josephs Joseph E Parisi David S Knopman Ronald C Petersen John R Hodges Olivier Piguet Ethan G Geier Jennifer S Yokoyama Robert A Rissman Ekaterina Rogaeva Julia Keith Lorne Zinman Maria Carmela Tartaglia Nigel J Cairns Carlos Cruchaga Bernardino Ghetti Julia Kofler Oscar L Lopez Thomas G Beach Thomas Arzberger Jochen Herms Lawrence S Honig Jean Paul Vonsattel Glenda M Halliday John B Kwok Charles L White Marla Gearing Jonathan Glass Sara Rollinson Stuart Pickering-Brown Jonathan D Rohrer John Q Trojanowski Vivianna Van Deerlin Eileen H Bigio Claire Troakes Safa Al-Sarraj Yan Asmann Bruce L Miller Neill R Graff-Radford Bradley F Boeve William W Seeley Ian R A Mackenzie John C van Swieten Dennis W Dickson Joanna M Biernacka Rosa Rademakers

Acta Neuropathol 2019 Feb 9. Epub 2019 Feb 9.

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

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25. Read More

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http://link.springer.com/10.1007/s00401-019-01962-9
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http://dx.doi.org/10.1007/s00401-019-01962-9DOI Listing
February 2019
14 Reads

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia.

Acta Neuropathol 2019 Mar 7;137(3):413-436. Epub 2019 Feb 7.

Department of Neurobiology and Neurology, Barrow Neurological Institute, 350 W. Thomas St, Phoenix, AZ, 85013, USA.

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD -) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD - cases. Read More

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http://link.springer.com/10.1007/s00401-019-01965-6
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http://dx.doi.org/10.1007/s00401-019-01965-6DOI Listing
March 2019
4 Reads
10.762 Impact Factor

Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer's disease.

Acta Neuropathol 2019 May 7;137(5):801-823. Epub 2019 Feb 7.

Faculté de pharmacie, Université Laval, Quebec, QC, Canada.

Several pieces of evidence suggest that blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD), exemplified by the frequent occurrence of cerebral amyloid angiopathy (CAA) and the defective clearance of Aβ peptides. However, the specific role of brain microvascular cells in these anomalies remains elusive. In this study, we validated by Western, ELISA and immunofluorescence analyses a procedure to generate microvasculature-enriched fractions from frozen samples of human cerebral cortex. Read More

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http://dx.doi.org/10.1007/s00401-019-01967-4DOI Listing
May 2019
7 Reads

Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo.

Acta Neuropathol 2019 Apr 5;137(4):599-617. Epub 2019 Feb 5.

Biomedical Research Institute, Hasselt University, 3500, Hasselt, Belgium.

Brains of Alzheimer's disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3-ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3-ASC inflammasome (Halle et al. Read More

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http://dx.doi.org/10.1007/s00401-018-01957-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426830PMC
April 2019
5 Reads