Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues
This report should aid diagnosis and thus the clinical management and genetic counseling ofMTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 6, 2017 Category: Neurology Source Type: research

Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood
AbstractWhereas microglia involvement in virtually all brain diseases is well accepted their role in the control of homeostasis in the central nervous system (CNS) is mainly thought to be the maintenance of neuronal function through the formation, refinement, and monitoring of synapses in both the developing and adult brain. Although the prenatal origin as well as the neuron-centered function of cortical microglia has recently been elucidated, much less is known about a distinct amoeboid microglia population formerly described as the “fountain of microglia” that appears only postnatally in myelinated regions su...
Source: Acta Neuropathologica - July 6, 2017 Category: Neurology Source Type: research

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology
AbstractTwo hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spina...
Source: Acta Neuropathologica - June 23, 2017 Category: Neurology Source Type: research

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms
AbstractLeukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic re...
Source: Acta Neuropathologica - June 21, 2017 Category: Neurology Source Type: research

Same-day genomic and epigenomic diagnosis of brain tumors using real-time nanopore sequencing
AbstractMolecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes...
Source: Acta Neuropathologica - June 21, 2017 Category: Neurology Source Type: research

Parietal white matter lesions in Alzheimer ’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease
AbstractCerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer ’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investi gated differences in the composition...
Source: Acta Neuropathologica - June 21, 2017 Category: Neurology Source Type: research

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer ’s disease-like pathologies and cognitive deficits
AbstractThe mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3  × Tg-AD,APP+/−/PS1+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacologic...
Source: Acta Neuropathologica - June 19, 2017 Category: Neurology Source Type: research

Myelin regulatory factor drives remyelination in multiple sclerosis
AbstractRemyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) i...
Source: Acta Neuropathologica - June 19, 2017 Category: Neurology Source Type: research

Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients
AbstractT cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific s...
Source: Acta Neuropathologica - June 17, 2017 Category: Neurology Source Type: research

IFN- β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis
AbstractDermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signatur...
Source: Acta Neuropathologica - June 16, 2017 Category: Neurology Source Type: research

The enteric nervous system is a potential autoimmune target in multiple sclerosis
AbstractMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS dege...
Source: Acta Neuropathologica - June 15, 2017 Category: Neurology Source Type: research

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging
Abstract[F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer ’s disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]- AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although t...
Source: Acta Neuropathologica - June 13, 2017 Category: Neurology Source Type: research

Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer ’s pathology
AbstractConventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of late onset sporadic Alzheimer ’s disease (LOAD). Mutations and/or differential expression of microglial specific receptors such as TREM2, CD33, and CR3 have been associated with strong increased risk for developing Alzheimer’s disease (AD). DAP12 (DNAX-activating protein 12)/TYROBP, a molecule localized to microglia, is a di rect partner/adapter for TREM2, CD33, and CR3. We and others have previously shown thatTYROBP expression is increased in AD patients and i...
Source: Acta Neuropathologica - June 13, 2017 Category: Neurology Source Type: research

Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington ’s disease
AbstractHuntington ’s disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of theHuntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutantHTT-induced degeneration in a fly HD model. We found that no...
Source: Acta Neuropathologica - June 7, 2017 Category: Neurology Source Type: research

Autism spectrum disorder: neuropathology and animal models
We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectu...
Source: Acta Neuropathologica - June 5, 2017 Category: Neurology Source Type: research

NG2 plays a role in neuroinflammation but is not expressed by immune cells
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 31, 2017 Category: Neurology Source Type: research

Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica
AbstractNeuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement ‘bystander mechanism’ to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to ast...
Source: Acta Neuropathologica - May 31, 2017 Category: Neurology Source Type: research

Modulation of IgG –FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 30, 2017 Category: Neurology Source Type: research

Synchronous gemistocytic astrocytoma IDH-mutant and oligodendroglioma IDH-mutant and 1p/19q-codeleted in a patient with CCDC26 polymorphism
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 26, 2017 Category: Neurology Source Type: research

Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 25, 2017 Category: Neurology Source Type: research

White matter injury in the preterm infant: pathology and mechanisms
AbstractThe human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation-dependent vulnerability of the oligodendrocyte (OL) lineage with selective dege...
Source: Acta Neuropathologica - May 22, 2017 Category: Neurology Source Type: research

Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson ’s disease brain
AbstractNeuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson ’s disease brain. Significant expression of this pathology closely reflected the regional pattern of...
Source: Acta Neuropathologica - May 19, 2017 Category: Neurology Source Type: research

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins
In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle ru pture following endocytosis. The ability to induce vesicle ru...
Source: Acta Neuropathologica - May 19, 2017 Category: Neurology Source Type: research

The multi-morbid old brain
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 16, 2017 Category: Neurology Source Type: research

In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers
AbstractA growing body of evidence suggests that a loss of chromosome 9 open reading frame 72 (C9ORF72) expression, formation of dipeptide-repeat proteins, and generation of RNA foci contribute to disease pathogenesis in amyotrophic lateral sclerosis and frontotemporal dementia. Although the levels ofC9ORF72 transcripts and dipeptide-repeat proteins have already been examined thoroughly, much remains unknown about the role of RNA foci inC9ORF72-linked diseases. As such, we performed a comprehensive RNA foci study in an extensive pathological cohort ofC9ORF72 expansion carriers (n = 63). We evaluated two brain reg...
Source: Acta Neuropathologica - May 15, 2017 Category: Neurology Source Type: research

HSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 13, 2017 Category: Neurology Source Type: research

Regulation of cathepsin D activity by the FTLD protein progranulin
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 10, 2017 Category: Neurology Source Type: research

Impact of multiple pathologies on the threshold for clinically overt dementia
AbstractLongitudinal clinical –pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development of Alzheimer’s disease (AD) and other forms of dementia. Older persons with A D pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These...
Source: Acta Neuropathologica - May 9, 2017 Category: Neurology Source Type: research

Erratum to: Antibody-mediated neutralization of myelin-associated EphrinB3 accelerates CNS remyelination
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 8, 2017 Category: Neurology Source Type: research

Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy
AbstractSporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (A β) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aβ deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 case s with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (...
Source: Acta Neuropathologica - May 6, 2017 Category: Neurology Source Type: research

Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model
AbstractClearance of amyloid-beta (A β) from the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Current studies mainly focus on the central approach of Aβ clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in cle aring brain-derived Aβ, suggesting that the peripheral approach of removing Aβ from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces bra...
Source: Acta Neuropathologica - May 5, 2017 Category: Neurology Source Type: research

Meningiomas induced by low-dose radiation carry structural variants of NF2 and a distinct mutational signature
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 4, 2017 Category: Neurology Source Type: research

Reappraisal of TDP-43 pathology in FTLD-U subtypes
AbstractFrontotemporal lobar degeneration with tau-negative, ubiquitin-immunoreactive (-ir) pathology (FTLD-U) is subclassified based on the type and cortical laminar distribution of neuronal inclusions. Following the discovery of the transactive response DNA-binding protein Mr 43 kD (TDP-43) as the ubiquitinated protein in most FTLD-U, the same pathological criteria have been used to classify FTLD cases based on TDP-43-ir changes. However, the fact that immunohistochemistry (IHC) for ubiquitin and TDP-43 each recognizes slightly different pathological changes in these cases means that the original FTLD-U subtype criteria ...
Source: Acta Neuropathologica - May 2, 2017 Category: Neurology Source Type: research

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer ’s disease
In conclusion,ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening ofABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 27, 2017 Category: Neurology Source Type: research

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients
In conclusion, DNA methylation analysis ofC9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 24, 2017 Category: Neurology Source Type: research

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis
AbstractIn the fatal disease —amyotrophic lateral sclerosis (ALS)—upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expres sed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate. Additionally...
Source: Acta Neuropathologica - April 13, 2017 Category: Neurology Source Type: research

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss
AbstractTranslation of the expanded (ggggcc)n repeat inC9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the ...
Source: Acta Neuropathologica - April 13, 2017 Category: Neurology Source Type: research

H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers
In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 11, 2017 Category: Neurology Source Type: research

Interactions of pathological proteins in neurodegenerative diseases
AbstractNeurodegenerative diseases such as Alzheimer ’s disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) have in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the mo st frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical present...
Source: Acta Neuropathologica - April 11, 2017 Category: Neurology Source Type: research

Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis
AbstractCortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and nat...
Source: Acta Neuropathologica - April 6, 2017 Category: Neurology Source Type: research

Roles of tau protein in health and disease
AbstractTau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review...
Source: Acta Neuropathologica - April 6, 2017 Category: Neurology Source Type: research

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
AbstractMutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay ons...
Source: Acta Neuropathologica - March 29, 2017 Category: Neurology Source Type: research

Amyloid- β accumulation in the CNS in human growth hormone recipients in the UK
AbstractHuman-to-human transmission of Creutzfeldt –Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of th...
Source: Acta Neuropathologica - March 27, 2017 Category: Neurology Source Type: research

Immunological memory to hyperphosphorylated tau in asymptomatic individuals
AbstractSeveral reports have described the presence of antibodies against Alzheimer ’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies re...
Source: Acta Neuropathologica - March 24, 2017 Category: Neurology Source Type: research

IRE1 signaling exacerbates Alzheimer ’s disease pathogenesis
AbstractAltered proteostasis is a salient feature of Alzheimer ’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade...
Source: Acta Neuropathologica - March 24, 2017 Category: Neurology Source Type: research

Acknowledgement to referees
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 24, 2017 Category: Neurology Source Type: research

α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca 2+ homeostasis and mitochondrial ATP production
Abstractα-Synuclein is strongly linked to Parkinson’s disease but the molecular targets for its toxicity are not fully clear. However, many neuronal functions damaged in Parkinson’s disease are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling involves clo se physical associations between the two organelles that are mediated by binding of the integral ER protein vesicle-associated membrane protein-associated protein B (VAPB) to the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). VAPB and PTPIP51 thu s act a...
Source: Acta Neuropathologica - March 23, 2017 Category: Neurology Source Type: research

Identification of T cell target antigens in glioblastoma stem-like cells using an integrated proteomics-based approach in patient specimens
AbstractGlioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells —often referred to as glioblastoma stem-like cells (GSCs)—has been shown to contribute to disease recurrence. To target these cells personalized immunotherapy has gained a lot of interest, e.g. by reactivating pre-existing anti-tumor immune responses against GSC antigens. To identify T cell targ ets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination w...
Source: Acta Neuropathologica - March 22, 2017 Category: Neurology Source Type: research

Cryptic exon incorporation occurs in Alzheimer ’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43
AbstractAbnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found in Alzheimer ’ disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is no...
Source: Acta Neuropathologica - March 22, 2017 Category: Neurology Source Type: research

The spectrum of neuropathological changes associated with congenital Zika virus infection
In conclusion, we characterized the destructive and malformative consequences of ZIKV in the nervous system, as reflected in the topography and severity of lesions, anatomic localization of the virus, and timing of infection during gestation. Our findings indicate a developmental vulnerability of the immature CNS, and shed light on possible mech anisms of brain injury of this newly recognized public health threat. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 22, 2017 Category: Neurology Source Type: research