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Acta Neuropathologica

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https://www.readbyqxmd.com/read/28341999/immunological-memory-to-hyperphosphorylated-tau-in-asymptomatic-individuals
#1
Gabriel Pascual, Jehangir S Wadia, Xueyong Zhu, Elissa Keogh, Başak Kükrer, Jeroen van Ameijde, Hanna Inganäs, Berdien Siregar, Gerrard Perdok, Otto Diefenbach, Tariq Nahar, Imke Sprengers, Martin H Koldijk, Els C Brinkman-van der Linden, Laura A Peferoen, Heng Zhang, Wenli Yu, Xinyi Li, Michelle Wagner, Veronica Moreno, Julie Kim, Martha Costa, Kiana West, Zara Fulton, Lucy Chammas, Nancy Luckashenak, Lauren Fletcher, Trevin Holland, Carrie Arnold, R Anthony Williamson, Jeroen J Hoozemans, Adrian Apetri, Frederique Bard, Ian A Wilson, Wouter Koudstaal, Jaap Goudsmit
Several 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...
March 24, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28341998/ire1-signaling-exacerbates-alzheimer-s-disease-pathogenesis
#2
Claudia Duran-Aniotz, Victor Hugo Cornejo, Sandra Espinoza, Álvaro O Ardiles, Danilo B Medinas, Claudia Salazar, Andrew Foley, Ivana Gajardo, Peter Thielen, Takao Iwawaki, Wiep Scheper, Claudio Soto, Adrian G Palacios, Jeroen J M Hoozemans, Claudio Hetz
Altered 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...
March 24, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28337542/%C3%AE-synuclein-binds-to-the-er-mitochondria-tethering-protein-vapb-to-disrupt-ca-2-homeostasis-and-mitochondrial-atp-production
#3
Sébastien Paillusson, Patricia Gomez-Suaga, Radu Stoica, Daniel Little, Paul Gissen, Michael J Devine, Wendy Noble, Diane P Hanger, Christopher C J Miller
α-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 close 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)...
March 23, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28332095/identification-of-t-cell-target-antigens-in-glioblastoma-stem-like-cells-using-an-integrated-proteomics-based-approach-in-patient-specimens
#4
Carmen Rapp, Rolf Warta, Slava Stamova, Ali Nowrouzi, Christoph Geisenberger, Zoltan Gal, Saskia Roesch, Steffen Dettling, Simone Juenger, Mariana Bucur, Christine Jungk, Philip DaoTrong, Rezvan Ahmadi, Felix Sahm, David Reuss, Valentina Fermi, Esther Herpel, Volker Eckstein, Niels Grabe, Christoph Schramm, Markus A Weigand, Juergen Debus, Andreas von Deimling, Andreas Unterberg, Amir Abdollahi, Philipp Beckhove, Christel Herold-Mende
Glioblastoma (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 targets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination with a T cell activation assay...
March 22, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28332094/cryptic-exon-incorporation-occurs-in-alzheimer-s-brain-lacking-tdp-43-inclusion-but-exhibiting-nuclear-clearance-of-tdp-43
#5
Mingkuan Sun, William Bell, Katherine D LaClair, Jonathan P Ling, Heather Han, Yusuke Kageyama, Olga Pletnikova, Juan C Troncoso, Philip C Wong, Liam L Chen
Abnormal 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 not known...
March 22, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28332093/pathogenic-implications-of-distinct-patterns-of-iron-and-zinc-in-chronic-ms-lesions
#6
Bogdan F Popescu, Josa M Frischer, Samuel M Webb, Mylyne Tham, Reginald C Adiele, Christopher A Robinson, Patrick D Fitz-Gibbon, Stephen D Weigand, Imke Metz, Susan Nehzati, Graham N George, Ingrid J Pickering, Wolfgang Brück, Simon Hametner, Hans Lassmann, Joseph E Parisi, Guo Yong, Claudia F Lucchinetti
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis...
March 22, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28332092/the-spectrum-of-neuropathological-changes-associated-with-congenital-zika-virus-infection
#7
Leila Chimelli, Adriana S O Melo, Elyzabeth Avvad-Portari, Clayton A Wiley, Aline H S Camacho, Vania S Lopes, Heloisa N Machado, Cecilia V Andrade, Dione C A Dock, Maria Elisabeth Moreira, Fernanda Tovar-Moll, Patricia S Oliveira-Szejnfeld, Angela C G Carvalho, Odile N Ugarte, Alba G M Batista, Melania M R Amorim, Fabiana O Melo, Thales A Ferreira, Jacqueline R L Marinho, Girlene S Azevedo, Jeime I B F Leal, Rodrigo F Madeiro da Costa, Stevens Rehen, Monica B Arruda, Rodrigo M Brindeiro, Rodrigo Delvechio, Renato S Aguiar, Amilcar Tanuri
A major concern associated with ZIKV infection is the increased incidence of microcephaly with frequent calcifications in infants born from infected mothers. To date, postmortem analysis of the central nervous system (CNS) in congenital infection is limited to individual reports or small series. We report a comprehensive neuropathological study in ten newborn babies infected with ZIKV during pregnancy, including the spinal cords and dorsal root ganglia (DRG), and also muscle, pituitaries, eye, systemic organs, and placentas...
March 22, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28315956/axonal-transport-deficits-in-multiple-sclerosis-spiraling-into-the-abyss
#8
REVIEW
Robert van den Berg, Casper C Hoogenraad, Rogier Q Hintzen
The transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this system have been linked to a large number of neurological disorders. In multiple sclerosis (MS) and associated models such as experimental autoimmune encephalomyelitis (EAE), alterations in axonal transport have been shown to exist before neurodegeneration occurs. Genome-wide association (GWA) studies have linked several motor proteins to MS susceptibility, while neuropathological studies have shown accumulations of proteins and organelles suggestive for transport deficits...
March 18, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28293793/ultrasensitive-and-selective-detection-of-3-repeat-tau-seeding-activity-in-pick-disease-brain-and-cerebrospinal-fluid
#9
Eri Saijo, Bernardino Ghetti, Gianluigi Zanusso, Adrian Oblak, Jennifer L Furman, Marc I Diamond, Allison Kraus, Byron Caughey
The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10(-7)-10(-9)...
March 14, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28271184/shared-genetic-risk-between-corticobasal-degeneration-progressive-supranuclear-palsy-and-frontotemporal-dementia
#10
Jennifer S Yokoyama, Celeste M Karch, Chun C Fan, Luke W Bonham, Naomi Kouri, Owen A Ross, Rosa Rademakers, Jungsu Kim, Yunpeng Wang, Günter U Höglinger, Ulrich Müller, Raffaele Ferrari, John Hardy, Parastoo Momeni, Leo P Sugrue, Christopher P Hess, A James Barkovich, Adam L Boxer, William W Seeley, Gil D Rabinovici, Howard J Rosen, Bruce L Miller, Nicholas J Schmansky, Bruce Fischl, Bradley T Hyman, Dennis W Dickson, Gerard D Schellenberg, Ole A Andreassen, Anders M Dale, Rahul S Desikan
Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD...
March 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28258398/proteomic-differences-in-amyloid-plaques-in-rapidly-progressive-and-sporadic-alzheimer-s-disease
#11
Eleanor Drummond, Shruti Nayak, Arline Faustin, Geoffrey Pires, Richard A Hickman, Manor Askenazi, Mark Cohen, Tracy Haldiman, Chae Kim, Xiaoxia Han, Yongzhao Shao, Jiri G Safar, Beatrix Ueberheide, Thomas Wisniewski
Rapidly progressive Alzheimer's disease (rpAD) is a particularly aggressive form of Alzheimer's disease, with a median survival time of 7-10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer's disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer's disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n = 22 for each patient group) and protein expression differences were quantified...
March 4, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28255664/adult-infiltrating-gliomas-with-who-2016-integrated-diagnosis-additional-prognostic-roles-of-atrx-and-tert
#12
Melike Pekmezci, Terri Rice, Annette M Molinaro, Kyle M Walsh, Paul A Decker, Helen Hansen, Hugues Sicotte, Thomas M Kollmeyer, Lucie S McCoy, Gobinda Sarkar, Arie Perry, Caterina Giannini, Tarik Tihan, Mitchel S Berger, Joseph L Wiemels, Paige M Bracci, Jeanette E Eckel-Passow, Daniel H Lachance, Jennifer Clarke, Jennie W Taylor, Tracy Luks, John K Wiencke, Robert B Jenkins, Margaret R Wrensch
The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined...
March 2, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28247064/genome-wide-association-study-identifies-four-novel-loci-associated-with-alzheimer-s-endophenotypes-and-disease-modifiers
#13
Yuetiva Deming, Zeran Li, Manav Kapoor, Oscar Harari, Jorge L Del-Aguila, Kathleen Black, David Carrell, Yefei Cai, Maria Victoria Fernandez, John Budde, Shengmei Ma, Benjamin Saef, Bill Howells, Kuan-Lin Huang, Sarah Bertelsen, Anne M Fagan, David M Holtzman, John C Morris, Sungeun Kim, Andrew J Saykin, Philip L De Jager, Marilyn Albert, Abhay Moghekar, Richard O'Brien, Matthias Riemenschneider, Ronald C Petersen, Kaj Blennow, Henrik Zetterberg, Lennart Minthon, Vivianna M Van Deerlin, Virginia Man-Yee Lee, Leslie M Shaw, John Q Trojanowski, Gerard Schellenberg, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Elaine R Peskind, Ge Li, Antonio F Di Narzo, John S K Kauwe, Alison M Goate, Carlos Cruchaga
More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS)...
February 28, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28247063/misfolded-sod1-is-not-a-primary-component-of-sporadic-als
#14
Sandrine Da Cruz, Anh Bui, Shahram Saberi, Sandra K Lee, Jennifer Stauffer, Melissa McAlonis-Downes, Derek Schulte, Donald P Pizzo, Philippe A Parone, Don W Cleveland, John Ravits
A common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations...
February 28, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28243725/motor-neuron-intrinsic-and-extrinsic-mechanisms-contribute-to-the-pathogenesis-of-fus-associated-amyotrophic-lateral-sclerosis
#15
Jelena Scekic-Zahirovic, Hajer El Oussini, Sina Mersmann, Kevin Drenner, Marina Wagner, Ying Sun, Kira Allmeroth, Stéphane Dieterlé, Jérôme Sinniger, Sylvie Dirrig-Grosch, Frédérique René, Dorothee Dormann, Christian Haass, Albert C Ludolph, Clotilde Lagier-Tourenne, Erik Storkebaum, Luc Dupuis
Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype...
February 28, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28160067/tau-aggregation-influences-cognition-and-hippocampal-atrophy-in-the-absence-of-beta-amyloid-a-clinico-imaging-pathological-study-of-primary-age-related-tauopathy-part
#16
Keith A Josephs, Melissa E Murray, Nirubol Tosakulwong, Jennifer L Whitwell, David S Knopman, Mary M Machulda, Stephen D Weigand, Bradley F Boeve, Kejal Kantarci, Leonard Petrucelli, Val J Lowe, Clifford R Jack, Ronald C Petersen, Joseph E Parisi, Dennis W Dickson
We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82-92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies...
February 3, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28130640/expansion-of-the-classification-of-ftld-tdp-distinct-pathology-associated-with-rapidly-progressive-frontotemporal-degeneration
#17
Edward B Lee, Sílvia Porta, G Michael Baer, Yan Xu, EunRan Suh, Linda K Kwong, Lauren Elman, Murray Grossman, Virginia M-Y Lee, David J Irwin, Vivianna M Van Deerlin, John Q Trojanowski
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundant grains, and oligodendroglial inclusions...
January 27, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28130638/marginal-vitamin-a-deficiency-facilitates-alzheimer-s-pathogenesis
#18
Jiaying Zeng, Li Chen, Zhe Wang, Qian Chen, Zhen Fan, Hongpeng Jiang, Yili Wu, Lan Ren, Jie Chen, Tingyu Li, Weihong Song
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer's disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive...
January 27, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28091722/hyperphosphorylated-tau-causes-reduced-hippocampal-ca1-excitability-by-relocating-the-axon-initial-segment
#19
Robert John Hatch, Yan Wei, Di Xia, Jürgen Götz
Hyperphosphorylated tau has a critical role in tauopathies such as Alzheimer's disease and frontotemporal dementia, impairing neuronal function and eventually leading to neurodegeneration. A critical role for tau is supported by studies in transgenic mouse models that express the P301L tau mutation found in cases of familial frontotemporal dementia, with the accumulation of hyperphosphorylated tau in the hippocampus causing reductions in hippocampal long-term potentiation and impairments in spatial learning and memory...
January 16, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28083634/tau-interactome-mapping%C3%A2-based-identification-of-otub1-as-tau-deubiquitinase-involved-in-accumulation-of-pathological-tau-forms-in-vitro-and-in-vivo
#20
Peng Wang, Gerard Joberty, Arjan Buist, Alexandre Vanoosthuyse, Ilie-Cosmin Stancu, Bruno Vasconcelos, Nathalie Pierrot, Maria Faelth-Savitski, Pascal Kienlen-Campard, Jean-Noël Octave, Marcus Bantscheff, Gerard Drewes, Diederik Moechars, Ilse Dewachter
Dysregulated proteostasis is a key feature of a variety of neurodegenerative disorders. In Alzheimer's disease (AD), progression of symptoms closely correlates with spatiotemporal progression of Tau aggregation, with "early" oligomeric Tau forms rather than mature neurofibrillary tangles (NFTs) considered to be pathogenetic culprits. The ubiquitin-proteasome system (UPS) controls degradation of soluble normal and abnormally folded cytosolic proteins. The UPS is affected in AD and is identified by genomewide association study (GWAS) as a risk pathway for AD...
January 12, 2017: Acta Neuropathologica
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