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Acta Neuropathologica Communications

Sonia Mazzitelli, Fabia Filipello, Marco Rasile, Eliana Lauranzano, Chiara Starvaggi-Cucuzza, Matteo Tamborini, Davide Pozzi, Isabella Barajon, Toni Giorgino, Antonino Natalello, Michela Matteoli
Substantial data indicate that amyloid-β (Aβ), the major component of senile plaques, plays a central role in Alzheimer's Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although Aβ42 is a highly aggregating form of Aβ, the co-occurrence of shorter Aβ peptides might affect the aggregation potential of the Aβ pool. In this study we aimed to assess whether the structural behavior of human Aβ42 peptide inside the brain is influenced by the concomitant presence of N-terminal fragments produced by the proteolytic activity of glial cells...
October 10, 2016: Acta Neuropathologica Communications
Oyinkan Sofola-Adesakin, Mobina Khericha, Inge Snoeren, Leo Tsuda, Linda Partridge
Several species of β-amyloid peptides (Aβ) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aβ peptides. Several N-terminal modified Aβ peptides have also been identified in Alzheimer's disease (AD) brains, the most common of which is pyroglutamate-modified Aβ (AβpE3-42). AβpE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ1-42 deposition...
October 7, 2016: Acta Neuropathologica Communications
Chi Wang Ip, Ioannis U Isaias, Burak B Kusche-Tekin, Dennis Klein, Janos Groh, Aet O'Leary, Susanne Knorr, Takahiro Higuchi, James B Koprich, Jonathan M Brotchie, Klaus V Toyka, Andreas Reif, Jens Volkmann
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis...
October 3, 2016: Acta Neuropathologica Communications
Kentaro Hayashi, Yoko Mochizuki, Ryoko Takeuchi, Toshio Shimizu, Masahiro Nagao, Kazuhiko Watabe, Nobutaka Arai, Kiyomitsu Oyanagi, Osamu Onodera, Masaharu Hayashi, Hitoshi Takahashi, Akiyoshi Kakita, Eiji Isozaki
In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI...
September 30, 2016: Acta Neuropathologica Communications
Vishruti Makani, Bin Zhang, Heeoon Han, Yuemang Yao, Pierrik Lassalas, Kevin Lou, Ian Paterson, Virginia M Y Lee, John Q Trojanowski, Carlo Ballatore, Amos B Smith, Kurt R Brunden
Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies...
September 29, 2016: Acta Neuropathologica Communications
Krista J Spiller, Clark R Restrepo, Tahiyana Khan, Anna M Stieber, Linda K Kwong, John Q Trojanowski, Virginia M-Y Lee
In order to treat progressive paralysis in ALS patients, it is critical to develop a mouse that closely models human ALS in both pathology and also in the timing of these events. We have recently generated new TDP-43 bigenic mice (called rNLS8) with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (hTDP-43∆NLS) under the control of the NEFH promoter. Our previous studies characterized the pathology and disease course in young rNLS8 mice following induction of neuronal hTDP-43ΔNLS...
September 29, 2016: Acta Neuropathologica Communications
Annika Scheffold, Inge R Holtman, Sandra Dieni, Nieske Brouwer, Sarah-Fee Katz, Billy Michael Chelliah Jebaraj, Philipp J Kahle, Bastian Hengerer, André Lechel, Stephan Stilgenbauer, Erik W G M Boddeke, Bart J L Eggen, Karl-Lenhard Rudolph, Knut Biber
Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model)...
August 22, 2016: Acta Neuropathologica Communications
Thuy-Vi V Nguyen, Jennifer B Frye, Jacob C Zbesko, Kristina Stepanovic, Megan Hayes, Alex Urzua, Geidy Serrano, Thomas G Beach, Kristian P Doyle
No abstract text is available yet for this article.
2016: Acta Neuropathologica Communications
Sabine Sellner, Ricardo Paricio-Montesinos, Alena Spieß, Annette Masuch, Daniel Erny, Laura A Harsan, Dominik V Elverfeldt, Marius Schwabenland, Knut Biber, Ori Staszewski, Sergio Lira, Steffen Jung, Marco Prinz, Thomas Blank
Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1 (-/-) mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1 (+/-) or cx3cr1 (+/+) controls...
2016: Acta Neuropathologica Communications
Silke Herzer, Sascha Meldner, Klara Rehder, Hermann-Josef Gröne, Viola Nordström
Decreased neuronal insulin receptor (IR) signaling in Alzheimer's disease is suggested to contribute to synaptic loss and neurodegeneration. This work shows that alteration of membrane microdomains increases IR levels and signaling, as well as neuronal viability in AD models in vitro and in vivo. Neuronal membrane microdomains are highly enriched in gangliosides. We found that inhibition of glucosylceramide synthase (GCS), the key enzyme of ganglioside biosynthesis, increases viability of cortical neurons in 5xFAD mice, as well as in cultured neurons exposed to oligomeric amyloid-β-derived diffusible ligands (ADDLs)...
2016: Acta Neuropathologica Communications
Takayuki Kondo, Misato Funayama, Michiyo Miyake, Kayoko Tsukita, Takumi Era, Hitoshi Osaka, Takashi Ayaki, Ryosuke Takahashi, Haruhisa Inoue
No abstract text is available yet for this article.
2016: Acta Neuropathologica Communications
Thuy-Vi V Nguyen, Jennifer B Frye, Jacob C Zbesko, Kristina Stepanovic, Megan Hayes, Alex Urzua, Geidy Serrano, Thomas G Beach, Kristian P Doyle
This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response. Our data indicate that in both mouse strains, and humans, there is increased granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-12 p70 (IL-12p70), interferon gamma-induced protein-10 (IP-10), keratinocyte chemoattractant/interleukin-8 (KC/IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), and Tumor necrosis factor-α (TNF-α) in the infarct core during the acute time period...
2016: Acta Neuropathologica Communications
Matthew Nolan, Kevin Talbot, Olaf Ansorge
Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest...
2016: Acta Neuropathologica Communications
Masaki Takao, Nobuyoshi Hirose, Yasumichi Arai, Ban Mihara, Masaru Mimura
Supercentenarians (aged 110 years old or more) are extremely rare in the world population (the number of living supercentenarians is estimated as 47 in the world), and details about their neuropathological information are limited. Based on previous studies, centenarians (aged 100-109 years old) exhibit several types of neuropathological changes, such as Alzheimer's disease and Lewy body disease pathology, primary age-related tauopathy, TDP-43 pathology, and hippocampal sclerosis. In the present study, we provide results from neuropathological analyses of four supercentenarian autopsy cases using conventional and immunohistochemical analysis for neurodegenerative disorders...
2016: Acta Neuropathologica Communications
Daniel W Sirkis, Luke W Bonham, Renan E Aparicio, Ethan G Geier, Eliana Marisa Ramos, Qing Wang, Anna Karydas, Zachary A Miller, Bruce L Miller, Giovanni Coppola, Jennifer S Yokoyama
Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level...
2016: Acta Neuropathologica Communications
Annika M Bourgonje, Kiek Verrijp, Jan T G Schepens, Anna C Navis, Jolanda A F Piepers, Chantal B C Palmen, Monique van den Eijnden, Rob Hooft van Huijsduijnen, Pieter Wesseling, William P J Leenders, Wiljan J A J Hendriks
The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases...
2016: Acta Neuropathologica Communications
Paola Caporali, Francesco Bruno, Giampiero Palladino, Jessica Dragotto, Laura Petrosini, Franco Mangia, Robert P Erickson, Sonia Canterini, Maria Teresa Fiorenza
Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1 (nmf164) for sensorimotor development from postnatal day (PN) 3 to PN21...
2016: Acta Neuropathologica Communications
Margarita Olympiou, Irene Sargiannidou, Kyriaki Markoullis, Christos Karaiskos, Alexia Kagiava, Styliana Kyriakoudi, Charles K Abrams, Kleopas A Kleopa
X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset of CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions of systemic inflammation and metabolic stress. To clarify the underlying mechanisms of CNS phenotypes in CMT1X we studied a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) injection to compare wild type (WT), connexin32 (Cx32) knockout (KO), and KO T55I mice expressing the T55I Cx32 mutation associated with CNS phenotypes...
2016: Acta Neuropathologica Communications
Scott Ryall, Rahul Krishnatry, Anthony Arnoldo, Pawel Buczkowicz, Matthew Mistry, Robert Siddaway, Cino Ling, Sanja Pajovic, Man Yu, Joshua B Rubin, Juliette Hukin, Paul Steinbok, Ute Bartels, Eric Bouffet, Uri Tabori, Cynthia Hawkins
Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0...
2016: Acta Neuropathologica Communications
Johanna Rodhe, Miguel A Burguillos, Rocio M de Pablos, Edel Kavanagh, Annette Persson, Elisabet Englund, Tomas Deierborg, Jose L Venero, Bertrand Joseph
Ischemic stroke (caused by thrombosis, embolism or vasoconstriction) lead to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral macrophages, which contribute to an inflammatory response involved in regulation of the neuronal damage. We showed earlier that upon pro-inflammatory stimuli, the orderly activation of caspase-8 and caspase-3/7 regulates microglia activation through a protein kinase C-δ dependent pathway. Here, we present in vivo evidence for the activation of caspase-8 and caspase-3 in microglia/macrophages in post-mortem tissue from human ischemic stroke subjects...
2016: Acta Neuropathologica Communications
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