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Article: Olfactory Bulb and Amygdala Gene Expression Changes in Subjects Dying with COVID-19.

Piras, Ignazio S / Huentelman, Matthew J / Walker, Jessica E / Arce, Richard / Glass, Michael J / Vargas, Daisy / Sue, Lucia I / Intorcia, Anthony J / Nelson, Courtney M / Suszczewicz, Katsuko E / Borja, Claryssa L / Desforges, Marc / Deture, Michael / Dickson, Dennis W / Beach, Thomas G / Serrano, Geidy E

medRxiv : the preprint server for health sciences

2021

Abstract: In this study we conducted RNA sequencing on two brain regions (olfactory bulb and amygdala) from subjects who died from COVID-19 or who died of other causes. We found several-fold more transcriptional changes in the olfactory bulb than in the amygdala, ... ...

Abstract	In this study we conducted RNA sequencing on two brain regions (olfactory bulb and amygdala) from subjects who died from COVID-19 or who died of other causes. We found several-fold more transcriptional changes in the olfactory bulb than in the amygdala, consistent with our own work and that of others indicating that the olfactory bulb may be the initial and most common brain region infected. To some extent our results converge with pseudotime analysis towards common processes shared between the brain regions, possibly induced by the systemic immune reaction following SARS-CoV-2 infection. Changes in amygdala emphasized upregulation of interferon-related neuroinflammation genes, as well as downregulation of synaptic and other neuronal genes, and may represent the substrate of reported acute and subacute COVID-19 neurological effects. Additionally, and only in olfactory bulb, we observed an increase in angiogenesis and platelet activation genes, possibly associated with microvascular damages induced by neuroinflammation. Through coexpression analysis we identified two key genes (
Language	English
Publishing date	2021-09-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.09.12.21263291
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Article ; Online: rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies.

Croft, Cara L / Cruz, Pedro E / Ryu, Daniel H / Ceballos-Diaz, Carolina / Strang, Kevin H / Woody, Brittany M / Lin, Wen-Lang / Deture, Michael / Rodríguez-Lebrón, Edgardo / Dickson, Dennis W / Chakrabarty, Paramita / Levites, Yona / Giasson, Benoit I / Golde, Todd E

The Journal of experimental medicine

2019 Volume 216, Issue 3, Page(s) 539–555

Abstract: It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and ... ...

Abstract	It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer's and Parkinson's disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau. Notably, the tauopathy BSC model enables screening of small molecule therapeutics and tracking of neurodegeneration. More generally, the rAAV BSC "toolkit" enables efficient transduction and transgene expression from neurons, microglia, astrocytes, and oligodendrocytes, alone or in combination, with transgene expression lasting for many months. These rAAV-based BSC models provide a cost-effective and facile alternative to in vivo studies, and in the future can become a widely adopted methodology to explore physiological and pathological mechanisms related to brain function and dysfunction.
MeSH term(s)	Alzheimer Disease/pathology ; Alzheimer Disease/virology ; Animals ; Brain/metabolism ; Brain/pathology ; Brain/virology ; Dependovirus/genetics ; Drug Evaluation, Preclinical/methods ; Gene Expression ; Humans ; Mice, Inbred C3H ; Mice, Transgenic ; Microorganisms, Genetically-Modified ; Mutation ; Neurons/pathology ; Organ Culture Techniques ; Parkinson Disease/pathology ; Parkinson Disease/virology ; Transduction, Genetic ; Transgenes ; alpha-Synuclein/genetics ; tau Proteins/genetics
Chemical Substances	MAPT protein, human ; alpha-Synuclein ; tau Proteins
Language	English
Publishing date	2019-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20182184
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Article ; Online: Olfactory Bulb and Amygdala Gene Expression Changes in Subjects Dying with COVID-19

Piras, Ignazio S / Huentelman, Matt / Walker, Jessica / Arche, Richard / Glass, Michael / Vargas, Daisy / Sue, Lucia / Intorcia, Anthony / Nelson, Courtney / Suszczewicz, Katsuko / Borja, Claryssa / Desforges, Marc / Deture, Michael / Dicksond, Dennis / Beach, Thomas / Serrano, Geidy

medRxiv

Abstract	In this study we conducted RNA sequencing on two brain regions (olfactory bulb and amygdala) from subjects who died from COVID-19 or who died of other causes. We found several-fold more transcriptional changes in the olfactory bulb than in the amygdala, consistent with our own work and that of others indicating that the olfactory bulb may be the initial and most common brain region infected. To some extent our results converge with pseudotime analysis towards common processes shared between the brain regions, possibly induced by the systemic immune reaction following SARS-CoV-2 infection. Changes in amygdala emphasized upregulation of interferon-related neuroinflammation genes, as well as downregulation of synaptic and other neuronal genes, and may represent the substrate of reported acute and subacute COVID-19 neurological effects. Additionally, and only in olfactory bulb, we observed an increase in angiogenesis and platelet activation genes, possibly associated with microvascular damages induced by neuroinflammation. Through coexpression analysis we identified two key genes (CAMK2B for the synaptic neuronal network and COL1A2 for the angiogenesis/platelet network) that might be interesting potential targets to reverse the effects induced by SARS-CoV-2 infection. Finally, in olfactory bulb we detected an upregulation of olfactory and taste genes, possibly as a compensatory response to functional deafferentation caused by viral entry into primary olfactory sensory neurons. In conclusion, we were able to identify transcriptional profiles and key genes involved in neuroinflammation, neuronal reaction and olfaction induced by direct CNS infection and/or the systemic immune response to SARS-CoV-2 infection.
Keywords	covid19
Language	English
Publishing date	2021-09-15
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.09.12.21263291
Database	COVID19

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Article: Structural insights into Alzheimer filament assembly pathways based on site-directed mutagenesis and S-glutathionylation of three-repeat neuronal Tau protein.

Dinoto, Luca / Deture, Michael A / Purich, Daniel L

Microscopy research and technique

2005 Volume 67, Issue 3-4, Page(s) 156–163

Abstract: Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary ... ...

Abstract	Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amino Acid Sequence ; Humans ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Microtubule-Associated Proteins/ultrastructure ; Microtubules/metabolism ; Microtubules/ultrastructure ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/ultrastructure ; Phosphorylation ; Protein Binding ; tau Proteins/genetics ; tau Proteins/metabolism ; tau Proteins/ultrastructure
Chemical Substances	Microtubule-Associated Proteins ; tau Proteins
Language	English
Publishing date	2005-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1099714-3
ISSN	1097-0029 ; 1059-910X
ISSN (online)	1097-0029
ISSN	1059-910X
DOI	10.1002/jemt.20195
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Article ; Online: Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins.

Carlomagno, Yari / Zhang, Yongjie / Davis, Mary / Lin, Wen-Lang / Cook, Casey / Dunmore, Judy / Tay, William / Menkosky, Kyle / Cao, Xiangkun / Petrucelli, Leonard / Deture, Michael

PloS one

2014 Volume 9, Issue 3, Page(s) e90452

Abstract: Background: Trans-activation Response DNA-binding Protein-43 (TDP-43) lesions are observed in Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration with ubiquitin inclusions (FTLD-TDP) and 25-50% of Alzheimer's Disease (AD) cases. These ...

Abstract	Background: Trans-activation Response DNA-binding Protein-43 (TDP-43) lesions are observed in Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration with ubiquitin inclusions (FTLD-TDP) and 25-50% of Alzheimer's Disease (AD) cases. These abnormal protein inclusions are composed of either amorphous TDP-43 aggregates or highly ordered filaments. The filamentous TDP-43 accumulations typically contain clean 10-12 nm filaments though wider 18-20 nm coated filaments may be observed. The TDP-43 present within these lesions is phosphorylated, truncated and ubiquitinated, and these modifications appear to be abnormal as they are linked to both a cellular heat shock response and microglial activation. The mechanisms associated with this abnormal TDP-43 accumulation are believed to result in a loss of TDP-43 function, perhaps due to the post-translational modifications or resulting from physical sequestration of the TDP-43. The formation of TDP-43 inclusions involves cellular translocation and conversion of TDP-43 into fibrillogenic forms, but the ability of these accumulations to sequester normal TDP-43 and propagate this behavior between neurons pathologically is mostly inferred. The lack of methodology to produce soluble full length TDP-43 and recapitulate this polymerization into filaments as observed in disease has limited our understanding of these pathogenic cascades. Results: The protocols described here generate soluble, full-length and untagged TDP-43 allowing for a direct assessment of the impact of various posttranslational modifications on TDP-43 function. We demonstrate that Casein Kinase II (CKII) promotes the polymerization of this soluble TDP-43 into 10 nm diameter filaments that resemble the most common TDP-43 structures observed in disease. Furthermore, these filaments are recognized as abnormal by Heat Shock Proteins (HSPs) which can inhibit TDP-43 polymerization or directly promote TDP-43 filament depolymerization. Conclusion: These findings demonstrate CKII induces polymerization of soluble TDP-43 into filaments and Hsp90 promotes TDP-43 filament depolymerization. These findings provide rational for potential therapeutic intervention at these points in TDP-43 proteinopathies.
MeSH term(s)	Animals ; Casein Kinase II/pharmacology ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/isolation & purification ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/metabolism ; Frontotemporal Lobar Degeneration/pathology ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Inclusion Bodies/drug effects ; Inclusion Bodies/metabolism ; Inclusion Bodies/ultrastructure ; Mice ; Phosphorylation/drug effects ; Polymerization/drug effects ; Protein Aggregation, Pathological/metabolism ; Reproducibility of Results ; Solubility
Chemical Substances	DNA-Binding Proteins ; HSP90 Heat-Shock Proteins ; Casein Kinase II (EC 2.7.11.1)
Language	English
Publishing date	2014-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0090452
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease.

Serrano, Geidy E / Walker, Jessica E / Arce, Richard / Glass, Michael J / Vargas, Daisy / Sue, Lucia I / Intorcia, Anthony J / Nelson, Courtney M / Oliver, Javon / Papa, Jaclyn / Russell, Aryck / Suszczewicz, Katsuko E / Borja, Claryssa I / Belden, Christine / Goldfarb, Danielle / Shprecher, David / Atri, Alireza / Adler, Charles H / Shill, Holly A /

Driver-Dunckley, Erika / Mehta, Shyamal H / Readhead, Benjamin / Huentelman, Matthew J / Peters, Joseph L / Alevritis, Ellie / Bimi, Christian / Mizgerd, Joseph P / Reiman, Eric M / Montine, Thomas J / Desforges, Marc / Zehnder, James L / Sahoo, Malaya K / Zhang, Haiyu / Solis, Daniel / Pinsky, Benjamin A / Deture, Michael / Dickson, Dennis W / Beach, Thomas G

medRxiv : the preprint server for health sciences

2021

Abstract: The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, ...

Abstract	The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal β-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.
Language	English
Publishing date	2021-02-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.02.15.21251511
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression.

Hamano, Tadanori / Gendron, Tania F / Causevic, Ena / Yen, Shu-Hui / Lin, Wen-Lang / Isidoro, Ciro / Deture, Michael / Ko, Li-wen

The European journal of neuroscience

2008 Volume 27, Issue 5, Page(s) 1119–1130

Abstract: The intracellular assembly of tau aggregates is a pathological hallmark shared by Alzheimer's disease and other neurodegenerative disorders known collectively as tauopathies. To model how tau fibrillogenesis evolves in tauopathies, we previously ... ...

Abstract	The intracellular assembly of tau aggregates is a pathological hallmark shared by Alzheimer's disease and other neurodegenerative disorders known collectively as tauopathies. To model how tau fibrillogenesis evolves in tauopathies, we previously established transfectant M1C cultures from human neuroblastoma BE(2)-M17D cells that inducibly express human tau. In the present study, these cells were used to determine the role of the autophagic-lysosomal system in the degradation and aggregation of wild-type tau. Tau induction for 5 days led to the accumulation of tau with nominal assembly of tau aggregates within cells. When the lysosomotropic agent, chloroquine (CQ), was added following the termination of tau induction, tau clearance was delayed. Decreased tau truncation and increased levels of intact tau were observed. When present during tau induction, CQ led to tau accumulation and promoted the formation of sarkosyl-insoluble aggregates containing both truncated and full-length tau. CQ treatment significantly decreased the activities of cathepsins D, B and L, and the inhibition of cathepsins B and L mimicked the effect of CQ and increased tau levels in cells. Additionally, exposure of cells to the autophagy inhibitor, 3-methyladenine, led to tau accumulation and aggregation. These results suggest that the autophagic-lysosomal system plays a role in the clearance of tau, and that dysfunction of this system results in the formation of tau oligomers and insoluble aggregates.
MeSH term(s)	Autophagy/genetics ; Cell Line, Tumor ; Cells, Cultured ; Gene Expression Regulation/physiology ; Humans ; Lysosomes/genetics ; Lysosomes/metabolism ; Lysosomes/pathology ; Protein Binding/genetics ; Tauopathies/genetics ; Tauopathies/metabolism ; Tauopathies/pathology ; Transfection/methods ; tau Proteins/biosynthesis ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2008-03
Publishing country	France
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/j.1460-9568.2008.06084.x
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Article ; Online: Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration.

Adams, Stephanie J / Crook, Richard J P / Deture, Michael / Randle, Suzanne J / Innes, Amy E / Yu, Xin Z / Lin, Wen-Lang / Dugger, Brittany N / McBride, Melinda / Hutton, Mike / Dickson, Dennis W / McGowan, Eileen

The American journal of pathology

2009 Volume 175, Issue 4, Page(s) 1598–1609

Abstract: Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene ... ...

Abstract	Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies.
MeSH term(s)	Aging/pathology ; Animals ; Axons/pathology ; Axons/ultrastructure ; Breeding ; Chromosomes, Artificial, Bacterial/genetics ; Gene Expression Regulation ; Genetic Vectors/genetics ; Genome/genetics ; Mice ; Mice, Transgenic ; Myelin Sheath/pathology ; Myelin Sheath/ultrastructure ; Nerve Degeneration/complications ; Nerve Degeneration/pathology ; Phosphorylation ; Solubility ; Tauopathies/complications ; Tauopathies/pathology ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2009-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.2353/ajpath.2009.090462
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Article ; Online: Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease

Serrano, Geidy E / Walker, Jessica E. / Arce, Richard / Glass, Michael J / Vargas, Daisy / Sue, Lucia / Intorcia, Anthony J / Nelson, Courtney M. / Oliver, Javon / Papa, Jaclyn / Russell, Aryck / Suszczewicz, Katsuko E. / Borja, Claryssa / Belden, Christine / Goldfarb, Danielle / Shprecher, David / Atri, Alireza / Adler, Charles H. / Shill, Holly A /

Driver-Dunckley, Erika / Mehta, Shyamal H. / Readhead, Benjamin / Huentelman, Matthew J / Peters, Joseph L. / Bimi, Christian / Mizgerd, Joseph P. / Reiman, Eric M. / Montine, Thomas J. / Desforges, Marc / Zehnder, James L. / Sahoo, Malaya K. / Zhang, Haiyu / Solis, Daniel / Pinsky, Benjamin A. / Deture, Michael / Dickson, Dennis W. / Beach, Thomas G.

medRxiv

Abstract	The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal B-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.
Keywords	covid19
Language	English
Publishing date	2021-02-18
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.02.15.21251511
Database	COVID19

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Article: Assembly of filamentous tau aggregates in human neuronal cells.

Ko, Li-Wen / Rush, Toni / Sahara, Naruhiko / Kersh, Jay S / Easson, Colin / Deture, Michael / Lin, Wen-Lang / Connor, Yamicia D / Yen, Shu-Hui C

Journal of Alzheimer's disease : JAD

2005 Volume 6, Issue 6, Page(s) 605–22; discussion 673–81

Abstract: Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as ... ...

Abstract	Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as tauopathies. Formation of such fibril inclusions, consisting of hyperphosphorylated tau in multiple isoforms, correlates with the severity of cognitive decline in AD. How neurofibrillary pathology evolves in tauopathy remains unclear at present, but availability of a cellular model with robust tau aggregation will permit experimental scrutiny of the mechanistic process leading to such neurodegeneration. Through the use of a serial transfection strategy in conjunction with a tau minigene construct, we succeeded in generating conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in isoforms 4R0N, 3R1N and 4R1N via TetOff and ecdysone inducible expression mechanisms. Such transgenic overexpression of tau in multiple isoforms facilitated the assembly of filamentous tau aggregates that exhibit immunoreactivities, physicochemical properties, and ultrastructural attributes reminiscent of those found in human tauopathies. The conditional tau transfectants thus provide us with a useful tool to elucidate the molecular and cellular events leading to neurofibrillary degeneration and a convenient means to test hypothetical mechanisms implicated in the etiopathogenesis of AD and related tauopathies.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Antibodies, Monoclonal/immunology ; Brain/immunology ; Brain/metabolism ; Brain/pathology ; Cell Aggregation/genetics ; Clone Cells ; Cognition Disorders/genetics ; Cognition Disorders/pathology ; DNA Primers ; Fluorescent Antibody Technique ; Humans ; Immunoblotting ; Immunoglobulin G/immunology ; Microtubule-Associated Proteins/metabolism ; Nerve Degeneration/genetics ; Nerve Degeneration/metabolism ; Nerve Degeneration/pathology ; Neurofibrillary Tangles/immunology ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Neurons/immunology ; Neurons/metabolism ; Neurons/pathology ; Phosphorylation ; Transfection ; tau Proteins/genetics ; tau Proteins/immunology ; tau Proteins/metabolism
Chemical Substances	Antibodies, Monoclonal ; DNA Primers ; Immunoglobulin G ; Microtubule-Associated Proteins ; tau Proteins
Language	English
Publishing date	2005-01-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/jad-2004-6605
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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito