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Acta Neuropathologica Communications

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https://www.readbyqxmd.com/read/30005699/rac1-activation-links-tau-hyperphosphorylation-and-a%C3%AE-dysmetabolism-in-alzheimer-s-disease
#1
Mirta Borin, Claudia Saraceno, Marcella Catania, Erika Lorenzetto, Valeria Pontelli, Anna Paterlini, Silvia Fostinelli, Anna Avesani, Giuseppe Di Fede, Gianluigi Zanusso, Luisa Benussi, Giuliano Binetti, Simone Zorzan, Roberta Ghidoni, Mario Buffelli, Silvia Bolognin
One of the earliest pathological features characterizing Alzheimer's disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls...
July 13, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/30005693/doublecortin-expressing-cell-types-in-temporal-lobe-epilepsy
#2
Joan Y W Liu, Mar Matarin, Cheryl Reeves, Andrew W McEvoy, Anna Miserocchi, Pamela Thompson, Sanjay M Sisodiya, Maria Thom
Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls...
July 13, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/30001207/enhancement-of-therapeutic-potential-of-a-naturally-occurring-human-antibody-targeting-a-phosphorylated-ser-422-containing-epitope-on-pathological-tau
#3
Jeroen van Ameijde, Rosa Crespo, Roosmarijn Janson, Jarek Juraszek, Berdien Siregar, Hanneke Verveen, Imke Sprengers, Tariq Nahar, Jeroen J Hoozemans, Stefan Steinbacher, Roland Willems, Lore Delbroek, Marianne Borgers, Koen Dockx, Kristof Van Kolen, Marc Mercken, Gabriel Pascual, Wouter Koudstaal, Adrian Apetri
Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency...
July 12, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29986767/sporadic-parkinson-s-disease-derived-neuronal-cells-show-disease-specific-mrna-and-small-rna-signatures-with-abundant-deregulation-of-pirnas
#4
Markus Schulze, Annika Sommer, Sonja Plötz, Michaela Farrell, Beate Winner, Janina Grosch, Jürgen Winkler, Markus J Riemenschneider
Differentiated neurons established via iPSCs from patients that suffer from familial Parkinson's disease (PD) have allowed insights into the mechanisms of neurodegeneration. In the larger cohort of patients with sporadic PD, iPSC based information on disease specific cellular phenotypes is rare. We asked whether differences may be present on genomic and epigenomic levels and performed a comprehensive transcriptomic and epigenomic analysis of fibroblasts, iPSCs and differentiated neuronal cells of sporadic PD-patients and controls...
July 10, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29976255/ablation-of-tau-causes-an-olfactory-deficit-in-a-murine-model-of-parkinson-s-disease
#5
Leah C Beauchamp, Jacky Chan, Lin W Hung, Benjamin S Padman, Laura J Vella, Xiang M Liu, Bradley Coleman, Ashley I Bush, Michael Lazarou, Andrew F Hill, Laura Jacobson, Kevin J Barnham
Parkinson's disease is diagnosed upon the presentation of motor symptoms, resulting from substantial degeneration of dopaminergic neurons in the midbrain. Prior to diagnosis, there is a lengthy prodromal stage in which non-motor symptoms, including olfactory deficits (hyposmia), develop. There is limited information about non-motor impairments and there is a need for directed research into these early pathogenic cellular pathways that precede extensive dopaminergic death in the midbrain. The protein tau has been identified as a genetic risk factor in the development of sporadic PD...
July 5, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29973287/dipeptide-repeat-proteins-activate-a-heat-shock-response-found-in-c9orf72-als-ftld-patients
#6
Daniel A Mordes, Mercedes Prudencio, Lindsey D Goodman, Joseph R Klim, Rob Moccia, Francesco Limone, Olli Pietilainen, Kaitavjeet Chowdhary, Dennis W Dickson, Rosa Rademakers, Nancy M Bonini, Leonard Petrucelli, Kevin Eggan
A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration...
July 4, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29973279/the-age-of-onset-and-evolution-of-braak-tangle-stage-and-thal-amyloid-pathology-of-alzheimer-s-disease-in-individuals-with-down-syndrome
#7
Yvonne S Davidson, Andrew Robinson, Vee P Prasher, David M A Mann
While post mortem studies have identified the major cell types and functional systems affected in Alzheimer's disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal 'model system' in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored...
July 4, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29961428/activity-of-translation-regulator-eukaryotic-elongation-factor-2-kinase-is-increased-in-parkinson-disease-brain-and-its-inhibition-reduces-alpha-synuclein-toxicity
#8
Asad Jan, Brandon Jansonius, Alberto Delaidelli, Forum Bhanshali, Yi Andy An, Nelson Ferreira, Lisa M Smits, Gian Luca Negri, Jens C Schwamborn, Poul H Jensen, Ian R Mackenzie, Stefan Taubert, Poul H Sorensen
Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity...
July 2, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29958546/neuroimaging-pathological-correlations-of-18-f-thk5351-pet-in-progressive-supranuclear-palsy
#9
Aiko Ishiki, Ryuichi Harada, Hideaki Kai, Naomi Sato, Tomoko Totsune, Naoki Tomita, Shoichi Watanuki, Kotaro Hiraoka, Yoichi Ishikawa, Yoshihito Funaki, Ren Iwata, Shozo Furumoto, Manabu Tashiro, Hironobu Sasano, Tetsuyuki Kitamoto, Yukitsuka Kudo, Kazuhiko Yanai, Katsutoshi Furukawa, Nobuyuki Okamura, Hiroyuki Arai
Recent positron emission tomography (PET) studies have demonstrated the accumulation of tau PET tracer in the affected region of progressive supranuclear palsy (PSP) cases. To confirm the binding target of radiotracer in PSP, we performed an imaging-pathology correlation study in two autopsy-confirmed PSP patients who underwent [18 F]THK5351 PET before death. One patient with PSP Richardson syndrome showed elevated tracer retention in the globus pallidus and midbrain. In a patient with PSP-progressive nonfluent aphasia, [18 F]THK5351 retention also was observed in the cortical areas, particularly the temporal cortex...
June 29, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29958544/phosphorylation-of-different-tau-sites-during-progression-of-alzheimer-s-disease
#10
Joerg Neddens, Magdalena Temmel, Stefanie Flunkert, Bianca Kerschbaumer, Christina Hoeller, Tina Loeffler, Vera Niederkofler, Guenther Daum, Johannes Attems, Birgit Hutter-Paier
Alzheimer's disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls...
June 29, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29954445/non-inflammatory-tumor-microenvironment-of-diffuse-intrinsic-pontine-glioma
#11
Grant L Lin, Surya Nagaraja, Mariella G Filbin, Mario L Suvà, Hannes Vogel, Michelle Monje
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM)...
June 28, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29891013/sequential-stages-and-distribution-patterns-of-aging-related-tau-astrogliopathy-artag-in-the-human-brain
#12
Gabor G Kovacs, Sharon X Xie, John L Robinson, Edward B Lee, Douglas H Smith, Theresa Schuck, Virginia M-Y Lee, John Q Trojanowski
Aging-related tau astrogliopathy (ARTAG) describes tau pathology in astrocytes in different locations and anatomical regions. In the present study we addressed the question of whether sequential distribution patterns can be recognized for ARTAG or astroglial tau pathologies in both primary FTLD-tauopathies and non-FTLD-tauopathy cases. By evaluating 687 postmortem brains with diverse disorders we identified ARTAG in 455. We evaluated frequencies and hierarchical clustering of anatomical involvement and used conditional probability and logistic regression to model the sequential distribution of ARTAG and astroglial tau pathologies across different brain regions...
June 11, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29890994/network-based-analysis-of-oligodendrogliomas-predicts-novel-cancer-gene-candidates-within-the-region-of-the-1p-19q-co-deletion
#13
Josef Gladitz, Barbara Klink, Michael Seifert
Oligodendrogliomas are primary human brain tumors with a characteristic 1p/19q co-deletion of important prognostic relevance, but little is known about the pathology of this chromosomal mutation. We developed a network-based approach to identify novel cancer gene candidates in the region of the 1p/19q co-deletion. Gene regulatory networks were learned from gene expression and copy number data of 178 oligodendrogliomas and further used to quantify putative impacts of differentially expressed genes of the 1p/19q region on cancer-relevant pathways...
June 11, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29880060/proteomic-analysis-of-medulloblastoma-reveals-functional-biology-with-translational-potential
#14
Samuel Rivero-Hinojosa, Ling San Lau, Mojca Stampar, Jerome Staal, Huizhen Zhang, Heather Gordish-Dressman, Paul A Northcott, Stefan M Pfister, Michael D Taylor, Kristy J Brown, Brian R Rood
Genomic characterization has begun to redefine diagnostic classifications of cancers. However, it remains a challenge to infer disease phenotypes from genomic alterations alone. To help realize the promise of genomics, we have performed a quantitative proteomics investigation using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and 41 tissue samples spanning the 4 genomically based subgroups of medulloblastoma and control cerebellum. We have identified and quantitated thousands of proteins across these groups and find that we are able to recapitulate the genomic subgroups based upon subgroup restricted and differentially abundant proteins while also identifying subgroup specific protein isoforms...
June 7, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29880043/the-genetic-landscape-of-ganglioglioma
#15
Melike Pekmezci, Javier E Villanueva-Meyer, Benjamin Goode, Jessica Van Ziffle, Courtney Onodera, James P Grenert, Boris C Bastian, Gabriel Chamyan, Ossama M Maher, Ziad Khatib, Bette K Kleinschmidt-DeMasters, David Samuel, Sabine Mueller, Anuradha Banerjee, Jennifer L Clarke, Tabitha Cooney, Joseph Torkildson, Nalin Gupta, Philip Theodosopoulos, Edward F Chang, Mitchel Berger, Andrew W Bollen, Arie Perry, Tarik Tihan, David A Solomon
Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas...
June 7, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29860944/proteomics-analysis-identifies-new-markers-associated-with-capillary-cerebral-amyloid-angiopathy-in-alzheimer-s-disease
#16
David C Hondius, Kristel N Eigenhuis, Tjado H J Morrema, Roel C van der Schors, Pim van Nierop, Marianna Bugiani, Ka Wan Li, Jeroen J M Hoozemans, August B Smit, Annemieke J M Rozemuller
Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits...
June 4, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29855382/loss-of-tmem106b-is-unable-to-ameliorate-frontotemporal-dementia-like-phenotypes-in-an-aav-mouse-model-of-c9orf72-repeat-induced-toxicity
#17
Alexandra M Nicholson, Xiaolai Zhou, Ralph B Perkerson, Tammee M Parsons, Jeannie Chew, Mieu Brooks, Mariely DeJesus-Hernandez, NiCole A Finch, Billie J Matchett, Aishe Kurti, Karen R Jansen-West, Emilie Perkerson, Lillian Daughrity, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Fenghua Hu, Tania F Gendron, Melissa E Murray, Dennis W Dickson, John D Fryer, Leonard Petrucelli, Rosa Rademakers
Loss-of-function mutations in progranulin (GRN) and a non-coding (GGGGCC)n hexanucleotide repeat expansions in C9ORF72 are the two most common genetic causes of frontotemporal lobar degeneration with aggregates of TAR DNA binding protein 43 (FTLD-TDP). TMEM106B encodes a type II transmembrane protein with unknown function. Genetic variants in TMEM106B associated with reduced TMEM106B levels have been identified as disease modifiers in individuals with GRN mutations and C9ORF72 expansions. Recently, loss of Tmem106b has been reported to protect the FTLD-like phenotypes in Grn-/- mice...
May 31, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29855361/environmental-enrichment-reverses-a%C3%AE-pathology-during-pregnancy-in-a-mouse-model-of-alzheimer-s-disease
#18
Stephanie Ziegler-Waldkirch, Karin Marksteiner, Johannes Stoll, Paolo d'Errico, Marina Friesen, Denise Eiler, Lea Neudel, Verena Sturn, Isabel Opper, Moumita Datta, Marco Prinz, Melanie Meyer-Luehmann
Several studies suggest that women have a higher risk to develop Alzheimer's disease (AD) than men. In particular, the number of pregnancies was shown to be a risk factor for AD and women with several pregnancies on average had an earlier onset of the disease, thus making childbearing a risk factor. However, the impact of being pregnant on Aβ plaque pathology and adult neurogenesis still remains elusive. Postmortem analysis revealed that pregnant 5xFAD transgenic mice had significantly more Aβ plaques in the hippocampus from G10 onwards and that the number of Ki67 and DCX positive cells dramatically decreased during the postpartum period...
May 31, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29855358/a-common-antigenic-motif-recognized-by-naturally-occurring-human-v-h-5-51-v-l-4-1-anti-tau-antibodies-with-distinct-functionalities
#19
Adrian Apetri, Rosa Crespo, Jarek Juraszek, Gabriel Pascual, Roosmarijn Janson, Xueyong Zhu, Heng Zhang, Elissa Keogh, Trevin Holland, Jay Wadia, Hanneke Verveen, Berdien Siregar, Michael Mrosek, Renske Taggenbrock, Jeroenvan Ameijde, Hanna Inganäs, Margot van Winsen, Martin H Koldijk, David Zuijdgeest, Marianne Borgers, Koen Dockx, Esther J M Stoop, Wenli Yu, Els C Brinkman-van der Linden, Kimberley Ummenthum, Kristof van Kolen, Marc Mercken, Stefan Steinbacher, Donata de Marco, Jeroen J Hoozemans, Ian A Wilson, Wouter Koudstaal, Jaap Goudsmit
Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH 5-51/VL 4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs...
May 31, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29855356/lrrk2-activity-does-not-dramatically-alter-%C3%AE-synuclein-pathology-in-primary-neurons
#20
Michael X Henderson, Chao Peng, John Q Trojanowski, Virginia M Y Lee
Mutations in leucine-rich repeat kinase (LRRK2) are the most common cause of heritable Parkinson's disease (PD), and the most common mutations in LRRK2 lead to elevated kinase activity. For these reasons, inhibitors targeting LRRK2 have been the subject of intense research and development. However, it has been difficult to develop preclinical models that recapitulate PD-relevant LRRK2 phenotypes. The primary pathology in PD is the Lewy body (LB), which is a cytoplasmic aggregate of α-synuclein. The recent demonstration that LB-like aggregates of α-synuclein can be induced in primary neurons has provided a robust model for testing genetic modifiers of PD-relevant aggregation and neurodegeneration...
May 31, 2018: Acta Neuropathologica Communications
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