Correction to: An update on the CNS manifestations of neurofibromatosis type 2
The article An update on the CNS manifestations of neurofibromatosis type 2, written by Shannon Coy, Rumana Rashid, Anat Stemmer ‑Rachamimov and Sandro Santagata, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 04 June 2019 without open access. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 20, 2019 Category: Neurology Source Type: research

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
AbstractTumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein s...
Source: Acta Neuropathologica - August 19, 2019 Category: Neurology Source Type: research

MYCN amplification drives an aggressive form of spinal ependymoma
AbstractSpinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showedMYCN amplification as a characteristic genet...
Source: Acta Neuropathologica - August 14, 2019 Category: Neurology Source Type: research

A β-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein
AbstractExtracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer’s disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical an d clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aβ and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice ...
Source: Acta Neuropathologica - August 14, 2019 Category: Neurology Source Type: research

Calling α-synuclein a prion is scientifically justifiable
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 12, 2019 Category: Neurology Source Type: research

Alpha-synuclein: prion or prion-like?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 12, 2019 Category: Neurology Source Type: research

The basis of cellular and regional vulnerability in Alzheimer ’s disease
AbstractAlzheimer ’s disease (AD) differentially and specifically affects brain regions and neuronal cell types in a predictable pattern. Damage to the brain appears to spread and worsens with time, taking over more regions and activating multiple stressors that can converge to promote vulnerability of certain cell types. At the same time, other cell types and brain regions remain intact in the face of this onslaught of neuropathology. Although neuropathologic descriptions of AD have been extensively expanded and mapped over the last several decades, our understanding of the mechanisms underlying how certain regions ...
Source: Acta Neuropathologica - August 7, 2019 Category: Neurology Source Type: research

Precise detection of low-level somatic mutation in resected epilepsy brain tissue
AbstractLow-level somatic mutations have been shown to be the major genetic etiology of intractable epilepsy. The extents thereof, however, have yet to be systematically and accurately explored in a large cohort of resected epilepsy brain tissues. Moreover, clinically useful and precise analysis tools for detecting low-level somatic mutations from unmatched formalin-fixed paraffin-embedded (FFPE) brain samples, the most clinically relevant samples, are still lacking. In total, 446 tissues samples from 232 intractable epilepsy patients with various brain pathologies were analyzed using deep sequencing (average read depth, 1...
Source: Acta Neuropathologica - August 3, 2019 Category: Neurology Source Type: research

Dipeptide repeat (DPR) pathology in the skeletal muscle of ALS patients with C9ORF72 repeat expansion
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 2, 2019 Category: Neurology Source Type: research

Neurotoxicology: an update on epidemiology, mechanisms, and pathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 1, 2019 Category: Neurology Source Type: research

Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
AbstractMicroglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection ...
Source: Acta Neuropathologica - July 30, 2019 Category: Neurology Source Type: research

Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer ’s disease patient brain samples
AbstractIdentification of multiple immune-related genetic risk factors for sporadic AD (sAD) have put the immune system center stage in mechanisms underlying this disorder. Comprehensive analysis of microglia in different stages of AD in human brains revealed microglia activation to follow the progression of AD neuropathological changes and requiring the co-occurrence of beta-Amyloid (A β) and tau pathology. Carriers of AD-associated risk variants in TREM2 (Triggering receptor expressed on myeloid cells 2) showed a reduction of plaque-associated microglia and a substantial increase in dystrophic neurites and overall p...
Source: Acta Neuropathologica - July 26, 2019 Category: Neurology Source Type: research

The neuropathology of fatal encephalomyelitis in human Borna virus infection
This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic scleros ing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 26, 2019 Category: Neurology Source Type: research

Splicing repression is a major function of TDP-43 in motor neurons
AbstractNuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression inDrosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repre...
Source: Acta Neuropathologica - July 22, 2019 Category: Neurology Source Type: research

C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
AbstractMicrosatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions inC9orf72 (100s –1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Par kinson’s disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediateC9orf72 repeats are a genet...
Source: Acta Neuropathologica - July 20, 2019 Category: Neurology Source Type: research

Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach
AbstractSeveral morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson ’s disease (PD), dystonia]. Using a...
Source: Acta Neuropathologica - July 17, 2019 Category: Neurology Source Type: research

Novel Alzheimer ’s disease risk genes: exhaustive investigation is paramount
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 12, 2019 Category: Neurology Source Type: research

Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions
AbstractMolecular markers have become pivotal in brain tumor diagnostics. Mutational analyses by targeted next-generation sequencing of DNA and array-based DNA methylation assessment with copy number analyses are increasingly being used in routine diagnostics. However, the broad variety of gene fusions occurring in brain tumors is marginally covered by these technologies and often only assessed by targeted assays. Here, we assessed the feasibility and clinical value of investigating gene fusions in formalin-fixed paraffin-embedded (FFPE) tumor tissues by next-generation mRNA sequencing in a routine diagnostic setting. Afte...
Source: Acta Neuropathologica - July 5, 2019 Category: Neurology Source Type: research

Alzheimer ’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation
In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enrich ed for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established compositez score. Our results showed that N...
Source: Acta Neuropathologica - June 27, 2019 Category: Neurology Source Type: research

Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1 , with recurrent co-mutation of PIK3CA and NF1
AbstractRosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), ...
Source: Acta Neuropathologica - June 27, 2019 Category: Neurology Source Type: research

Evidence for bidirectional and trans -synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats
In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat mo del with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pat hways (ENS, autonomic ganglia, intermediolat...
Source: Acta Neuropathologica - June 26, 2019 Category: Neurology Source Type: research

Oral and intravenous transmission of α-synuclein fibrils to mice
AbstractParkinson ’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphoryl ated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of &alpha...
Source: Acta Neuropathologica - June 22, 2019 Category: Neurology Source Type: research

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
AbstractNemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We ...
Source: Acta Neuropathologica - June 19, 2019 Category: Neurology Source Type: research

Cellular and regional vulnerability in frontotemporal tauopathies
AbstractThe frontotemporal tauopathies all deposit abnormal tau protein aggregates, but often of only certain isoforms and in distinguishing pathologies of five main types (neuronal Pick bodies, neurofibrillary tangles, astrocytic plaques, tufted astrocytes, globular glial inclusions and argyrophilic grains). In those with isoform specific tau aggregates glial pathologies are substantial, even though there is limited evidence that these cells normally produce tau protein. This review will assess the differentiating features and clinicopathological correlations of the frontotemporal tauopathies, the genetic predisposition f...
Source: Acta Neuropathologica - June 15, 2019 Category: Neurology Source Type: research

Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia
This study identifies CYP46A1 as a relevant therapeutic target not only for SCA3 but also for other SCAs. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 14, 2019 Category: Neurology Source Type: research

Neurotoxicity of pesticides
AbstractPesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes ...
Source: Acta Neuropathologica - June 13, 2019 Category: Neurology Source Type: research

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy
AbstractCerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer ’s disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster ...
Source: Acta Neuropathologica - June 10, 2019 Category: Neurology Source Type: research

Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy
AbstractParkinson ’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s d...
Source: Acta Neuropathologica - June 6, 2019 Category: Neurology Source Type: research

An update on the CNS manifestations of neurofibromatosis type 2
AbstractNeurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in theNF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neu...
Source: Acta Neuropathologica - June 4, 2019 Category: Neurology Source Type: research

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players
AbstractChronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugb...
Source: Acta Neuropathologica - June 1, 2019 Category: Neurology Source Type: research

Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model
AbstractParkinson ’s disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) ex pressing human, aggregation-prone truncated 1–120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is assoc...
Source: Acta Neuropathologica - May 31, 2019 Category: Neurology Source Type: research

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation
AbstractGranulovacuolar degeneration (GVD) is usually found in Alzheimer ’s disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9;N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9;N = 46), a...
Source: Acta Neuropathologica - May 29, 2019 Category: Neurology Source Type: research

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer ’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
AbstractThe genetic variant rs72824905-G (minor allele) in thePLCG2 gene was previously associated with a reduced Alzheimer ’s disease risk (AD). The role ofPLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (...
Source: Acta Neuropathologica - May 27, 2019 Category: Neurology Source Type: research

ALK-positive histiocytosis with KIF5B - ALK fusion in the central nervous system
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 22, 2019 Category: Neurology Source Type: research

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes
AbstractIn 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4  MB subtypes...
Source: Acta Neuropathologica - May 10, 2019 Category: Neurology Source Type: research

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma
AbstractDNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1 –3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 m eningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylati...
Source: Acta Neuropathologica - May 8, 2019 Category: Neurology Source Type: research

Lack of H3K27 trimethylation is associated with 1p/19q codeletion in diffuse gliomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr 348 phosphorylation
In conclusion, our data support the idea that BIN1 modulates the AD risk through an intrica te regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

Revisiting the utility of TDP-43 immunoreactive (TDP-43-ir) pathology to classify FTLD-TDP subtypes
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 7, 2019 Category: Neurology Source Type: research

RhoA regulates translation of the Nogo-A decoy SPARC in white matter-invading glioblastomas
This study demonstrates that the prevalent activation of AKT in gliomas increases the ER protein-folding capacity and enables tumor cells to utilize a side effect of RhoA activation: the perturbation of the IRE1 α-mediated decay of SPARC mRNA. Once translation is initiated, glioblastoma cells rapidly secrete SPARC to block Nogo-A from inhibiting migration via RhoA. By advanced ultramicroscopy for studying single-cell invasion in whole, undissected mouse brains, we show that gliomas require SPARC for invadi ng into white matter structures. SPARC depletion reduces tumor dissemination that significantly prolongs surviva...
Source: Acta Neuropathologica - May 6, 2019 Category: Neurology Source Type: research

Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis
AbstractThe limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35 –55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in t...
Source: Acta Neuropathologica - April 27, 2019 Category: Neurology Source Type: research

Molecular progression of SHH-activated medulloblastomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 27, 2019 Category: Neurology Source Type: research

Endogenous oligodendroglial alpha-synuclein and TPPP/p25 α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models
AbstractMultiple 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/p25 α. 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 different iated oligodendrocytes derived from WT, knockout (KO)-...
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling
AbstractSchwann 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. The data highlight for the first time that SC migrate preferentially along blood vessels in perivascular extracellular matrix (ECM), avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin signaling. Indeed, EphrinB3, enriched in myelin, interacts...
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Correction to: The origin, fate, and contribution of macrophages to spinal cord injury pathology
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. Ly6CHi, Cx3Cr1Lo, Ccr2Hi should have been associated with pro-inflammatory macrophages on the left, and Ly6CLo, Cx3Cr1Hi, Ccr2Lo should have been associated with anti-inflammatory macrophages on the right. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 22, 2019 Category: Neurology Source Type: research

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer ’s disease
AbstractAlzheimer ’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 activatio n 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. Single-nucle...
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

Selective vulnerability in α-synucleinopathies
In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the “death by a thousand cuts” profile of α-synucleinopath ies. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

Detection of AD-specific four repeat tau with deamidated asparagine residue 279-specific fraction purified from 4R tau polyclonal antibody
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 20, 2019 Category: Neurology Source Type: research

The new genetic landscape of Alzheimer ’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?
AbstractA 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. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approa...
Source: Acta Neuropathologica - April 13, 2019 Category: Neurology Source Type: research

Neurotoxicity of polychlorinated biphenyls and related organohalogens
AbstractHalogenated 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 outcom es have also been noted. Here, we review human studies of pren...
Source: Acta Neuropathologica - April 11, 2019 Category: Neurology Source Type: research