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; Yen, Shu Hui

doi:10.3233/jad-2004-6605

Cited by 30 publications

(62 citation statements)

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“…These included tissue morphogen pathways (wnt, fzd, Ssh, Hox, Notch), growh factor pathways (EGF, FGF, NGF, PDGF, BDGF) and axonal guidance pathways (semaphorins, netrins, ephrins and slit). Panel A: summarizes the results of GO based analysis of this proteome using the online String 9.05 program [187]. Proteins present in this dataset and absent from a control neuroblastoma exosomal dataset (638 proteins)…”

Section: Whither the Cell Cycle?mentioning

confidence: 99%

“…A proteome of 669 proteins from exosome samples taken from M1C neuroblastoma cells was identified by mass spectometic analysis as described [166]. Prescreening was done using a large panel of 616 AD associated proteins [187] and 1968 general neurodevelopmental proteins based on String interactors [188] with axonogenesis and morphogenesis-associated proteins. These included tissue morphogen pathways (wnt, fzd, Ssh, Hox, Notch), growh factor pathways (EGF, FGF, NGF, PDGF, BDGF) and axonal guidance pathways (semaphorins, netrins, ephrins and slit).…”

Section: Whither the Cell Cycle?mentioning

confidence: 99%

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Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

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Section: Whither the Cell Cycle?mentioning

confidence: 99%

Section: Whither the Cell Cycle?mentioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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“…Cell culture Transfectant M1C was established from human neuroblastoma BE [2]-M17D [8] as an inducible transfectant whereby conditional overexpressions of tau in distinct isoforms are regulated via separate inducible expression systems in a time-and dose-dependent fashion [5]. To simplify its utility in the current study on tau aggregation, we elicited expression of 4R0N tau only by using TetOff induction (tau concentration reaching 33.8 lmole/l after 5 days), making M1C behave like a single isoform transfectant.…”

Section: Methodsmentioning

confidence: 99%

“…Results from previous immunoblotting analyses [5] indicate that a 70-kD tau is an oligomeric assembly of tau fragments, that is resistant to b-mercaptoethanol (bME) reduction, in our cellular model. It probably plays a key role in tau aggregation because it is a putative precursor of high-molecularweight assemblies and, above all, a reliable indicator to predict such formation.…”

Section: Introductionmentioning

confidence: 92%

“…In previous studies, we developed a number of inducible tau transfectants [4][5][6] among which M1C overexpresses wild-type human brain tau in distinct isoforms via separate inducible mechanisms in a time-and dose-dependent manner [5]. Accumulation of tau from such overproduction precipitates aggregate assembly (demonstrable with immunoblotting) and formation of inclusions consisting of 12~22-nm tau fibrils [5]. Aside from its non-mutation nature, the culture system recapitulates, in a week or less, key features of NFD that take decades to emerge in AD and related tauopathies.…”

Section: Introductionmentioning

confidence: 99%

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Cytosine β-D-arabinofuranoside used as a Paradigm Modifier to Increase Production of Tau Aggregates in a Cellular Model of Tauopathy

Kulathingal

Yen

2006

Neurochem Res

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Intraneuronal deposition of filamentous tau is a hallmark of Alzheimer's disease (AD) and related tauopathies. We developed previously a cellular model recapitulating such tau anomaly and demonstrated therein consistent production of 70-kD tau. Importantly, the 70-kD species appears to derive from tau fragments with carboxy-terminal truncation and is larger than intact tau in size, suggesting the oligomeric nature in its assembly from tau. To generate the 70-kD tau in sufficient quantity for its characterization at the molecular level, we explored and demonstrated herein that cytosine beta-D-arabinofuranoside is a useful paradigm modifier to increase production of the 70-kD tau. Such oligomeric tau was enriched thereafter by immunoprecipitation to remove tau species with intact carboxy-terminus. Two-dimensional gel electrophoresis revealed that the 70-kD tau has an isoelectric point of 5.8-6.0. Future elucidation of key aggregates will provide valuable insights into the natural history of neurofibrillary degeneration and identify novel targets to develop therapeutic interventions.

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Inhibition of proteasome and Shaggy/Glycogen synthase kinase‐3β kinase prevents clearance of phosphorylated tau in Drosophila

Blard¹,

Frébourg²,

Campion³

et al. 2006

J of Neuroscience Research

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Tauopathies, including Alzheimer's disease (AD), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of abnormally phosphorylated tau protein. In AD brains, it has been shown that the level of abnormally phosphorylated tau is higher than in age-matched control brains, suggesting that abnormally phosphorylated tau is resistant to degradation. By using a Drosophila model of tauopathy, we studied the relationship between tau phosphorylation and degradation. We showed that in vivo reduction of proteasome activity results in an accumulation of high-molecular-weight forms of hyperphosphorylated tau. We also found that glycogen synthase kinase (GSK)-3beta-mediated hyperphosphorylated forms of tau are degradable by the proteasomal machinery. Unexpectedly, GSK-3beta inactivation resulted in a very large accumulation of high-molecular-weight species consisting of hyperphosphorylated tau, suggesting that, depending on the kinase(s) involved, tau phosphorylation state affects its degradation differently. We thus propose a model for tauopathies in which, depending on toxic challenges (e.g., oxidative stress, exposure to amyloid peptide, etc.), abnormal phosphorylation of tau by kinases distinct from GSK-3beta leads to progressive accumulation of hyperphosphorylated tau oligomers that are resistant to degradation.

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Assembly of filamentous tau aggregates in human neuronal cells

Cited by 30 publications

References 0 publications

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Cytosine β-D-arabinofuranoside used as a Paradigm Modifier to Increase Production of Tau Aggregates in a Cellular Model of Tauopathy

Inhibition of proteasome and Shaggy/Glycogen synthase kinase‐3β kinase prevents clearance of phosphorylated tau in Drosophila

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