scholarly journals Visualization of Tau–Tubulin Interaction in a Living Cell Using Bifluorescence Complementation Technique

2018 ◽  
Vol 19 (10) ◽  
pp. 2978 ◽  
Author(s):  
Seulgi Shin ◽  
Sungsu Lim ◽  
Hyeanjeong Jeong ◽  
Li Kwan ◽  
Yun Kim
Keyword(s):  
Neurodegenerative Disorders ◽  
Living Cell ◽  
Neuronal Degeneration ◽  
Cell Model ◽  
Chemical Stimulation ◽  
Aggregation Process ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
A Cell ◽  
Tau Aggregation

Tau is a neuron-specific microtubule-binding protein that stabilizes microtubules. It is generally thought that highly phosphorylated tau dissociates from microtubules and becomes insoluble aggregates, leading to neuronal degeneration. Due to the implication of tau aggregation in neurodegenerative disorders, including Alzheimer’s disease, great efforts have been made to identify the tau aggregation process. However, tau interaction with tubulin during the aggregation process remains largely unknown. To scrutinize the tau-tubulin interaction, we generated a cell model that enables visualization of the tau-tubulin interaction in a living cell using the Bifluorescence Complementation (BiFC) Technique. Upon diverse chemical stimulation that induced tau pathology, tau-tubulin BiFC cells showed significantly increased levels of BiFC fluorescence, indicating that tau aggregates together with tubulin. Our results suggest that tubulin should be considered as a key component in the tau aggregation process.

[P4-102]: CHARACTERISATION OF MOLECULAR MECHANISMS THAT ARE TRIGGERED AND CONTRIBUTE TO TAU PATHOLOGY IN A CELL MODEL OF TAU AGGREGATION

2017 ◽  
Vol 13 (7S_Part_27) ◽  
pp. P1297-P1297
Author(s):  
Emma Mead ◽  
Elena Ficulle ◽  
Charlotte Dunbar ◽  
Sarah Eversden ◽  
Michael J. O'Neill ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Model ◽  
Tau Pathology ◽  
A Cell ◽  
Tau Aggregation

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals A Simple Model to Study Tau Pathology

2016 ◽  
Vol 10 ◽  
pp. JEN.S25100 ◽  
Author(s):  
Alexander L. Houck ◽  
Félix Hernández ◽  
Jesús Ávila
Keyword(s):  
Cell Model ◽  
Tau Proteins ◽  
Human Embryonic Kidney ◽  
Tau Pathology ◽  
Pathological Conditions ◽  
293 Cells ◽  
Stable Manner ◽  
A Cell ◽  
Tau Kinases ◽  
Gsk3 Inhibitor

Tau proteins play a role in the stabilization of microtubules, but in pathological conditions, tauopathies, tau is modified by phosphorylation and can aggregate into aberrant aggregates. These aggregates could be toxic to cells, and different cell models have been used to test for compounds that might prevent these tau modifications. Here, we have used a cell model involving the overexpression of human tau in human embryonic kidney 293 cells. In human embryonic kidney 293 cells expressing tau in a stable manner, we have been able to replicate the phosphorylation of intracellular tau. This intracellular tau increases its own level of phosphorylation and aggregates, likely due to the regulatory effect of some growth factors on specific tau kinases such as GSK3. In these conditions, a change in secreted tau was observed. Reversal of phosphorylation and aggregation of tau was found by the use of lithium, a GSK3 inhibitor. Thus, we propose this as a simple cell model to study tau pathology in nonneuronal cells due to their viability and ease to work with.

scholarly journals Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

2021 ◽  
Vol 22 (18) ◽  
pp. 10145
Author(s):  
Giacomo Siano ◽  
Chiara Falcicchia ◽  
Nicola Origlia ◽  
Antonino Cattaneo ◽  
Cristina Di Primio
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Neuronal Degeneration ◽  
Synaptic Dysfunction ◽  
Cell Soma ◽  
Post Translational Modifications ◽  
Synaptic Homeostasis ◽  
Wide Range ◽  
And Function ◽  
Tau Aggregation

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.

scholarly journals Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation

Autophagy ◽  
2010 ◽  
Vol 6 (1) ◽  
pp. 182-183 ◽  
Author(s):  
Yipeng Wang ◽  
Marta Martinez-Vicente ◽  
Ulrike Krüger ◽  
Susmita Kaushik ◽  
Esther Wong ◽  
...  
Keyword(s):  
Cell Model ◽  
A Cell ◽  
Tau Aggregation ◽  
Chaperone Mediated Autophagy

Proteolytic processing of tau

2010 ◽  
Vol 38 (4) ◽  
pp. 955-961 ◽  
Author(s):  
Yipeng Wang ◽  
Sarika Garg ◽  
Eva-Maria Mandelkow ◽  
Eckhard Mandelkow
Keyword(s):  
Neurodegenerative Diseases ◽  
Therapeutic Approach ◽  
Cell Model ◽  
Proteolytic Processing ◽  
The Other ◽  
Promising Therapeutic Approach ◽  
A Cell ◽  
Ad Alzheimer’S Disease ◽  
Tau Aggregation ◽  
Tau Cleavage

Tau aggregation is a hallmark of several neurodegenerative diseases, including AD (Alzheimer's disease), although the mechanism underlying tau aggregation remains unclear. Recent studies show that the proteolysis of tau plays an important role in both tau aggregation and neurodegeneration. On one hand, truncation of tau may generate amyloidogenic tau fragments that initiate the aggregation of tau, which in turn can cause toxicity. On the other hand, truncation of tau may result in tau fragments which induce neurodegeneration through unknown mechanisms, independently of tau aggregation. Blocking the truncation of tau thus may represent a promising therapeutic approach for AD or other tauopathies. In the present paper, we summarize our data on tau cleavage in a cell model of tauopathy and major results on tau cleavage reported in the literature.

scholarly journals Oral (−)-Epicatechin Inhibits Progressive Tau Pathology in rTg4510 Mice Independent of Direct Actions at GSK3β

2021 ◽  
Vol 15 ◽  
Author(s):  
Katriona L. Hole ◽  
Lydia E. Staniaszek ◽  
Gayathri Menon Balan ◽  
Jody M. Mason ◽  
Jon T. Brown ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Amyloid Β ◽  
Paired Helical Filaments ◽  
Tau Pathology ◽  
Direct Inhibition ◽  
Plaque Pathology ◽  
A Cell ◽  
Tau Aggregation ◽  
Molecular Weight Form

Aggregation of the microtubule-associated protein tau into paired helical filaments (PHFs) and neurofibrillary tangles is a defining characteristic of Alzheimer’s Disease. Various plant polyphenols disrupt tau aggregation in vitro but display poor bioavailability and low potency, challenging their therapeutic translation. We previously reported that oral administration of the flavonoid (−)-epicatechin (EC) reduced Amyloid-β (Aβ) plaque pathology in APP/PS1 transgenic mice. Here, we investigated whether EC impacts on tau pathology, independent of actions on Aβ, using rTg4510 mice expressing P301L mutant tau. 4 and 6.5 months old rTg4510 mice received EC (∼18 mg/day) or vehicle (ethanol) via drinking water for 21 days and the levels of total and phosphorylated tau were assessed. At 4 months, tau appeared as two bands of ∼55 kDa, phosphorylated at Ser262 and Ser396 and was unaffected by exposure to EC. At 6.5 months an additional higher molecular weight form of tau was detected at ∼64 kDa which was phosphorylated at Ser262, Ser396 and additionally at the AT8 sites, indicative of the presence of PHFs. EC consumption reduced the levels of the ∼64 kDa tau species and inhibited phosphorylation at Ser262 and AT8 phosphoepitopes. Regulation of the key tau kinase glycogen synthase kinase 3β (GSK3β) by phosphorylation at Ser9 was not altered by exposure to EC in mice or primary neurons. Furthermore, EC did not significantly inhibit GSK3β activity at physiologically-relevant concentrations in a cell free assay. Therefore, a 21-day intervention with EC inhibits or reverses the development of tau pathology in rTg4510 mice independently of direct inhibition of GSK3β.

scholarly journals Acetylation of Tau Induces Alzheimer's Disease-Associated Tau in Transgenic Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 966-966
Author(s):  
Addison Ali ◽  
Kristeen Pareja ◽  
Tara Tracy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurodegenerative Disorder ◽  
Mossy Fibers ◽  
Tau Proteins ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Ca1 Region ◽  
Tau Aggregation

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by neurofibrillary tangles (NFTs) and amyloid beta plaques. These NFTs are made up of aggregated tau proteins. Tau is involved in stabilizing microtubules and does not usually display aggregation. Acetylation of tau protein causes an increase in tau aggregation but its role in AD progression is still not well understood. I hypothesized that enhanced acetylated tau results in an increase in AD-like tau pathology. To test this, a murine prion promoter-tauKQ transgene was injected into the mouse fertilized oocyte. The tauKQ mutation alters lysine to glutamine to mimic acetylation of tau. Nontransgenic mice were used as controls. AT8 and GT-38 antibodies were used in immunohistochemistry (IHC) to target phosphorylated tau and AD-associated tau, respectively. GT-38 is conformation-dependent and requires 3R and 4R tau isoforms which makes it specific to AD. Through immunofluorescence, increased phosphorylated tau was observed in the hippocampus of the tauKQ mice compared to the nontransgenic mice. I focused on the dentate gyrus, CA1 region, and the mossy fibers of the CA3 region since they are involved in many memory processes. Through chromogenic IHC, the tauKQ mice exhibited more 3R+4R tau isoform pathology in the mossy fibers than the nontransgenic mice. This data suggests that an acetylation mimic is sufficient to stimulate an abundance of AD-related tau pathology in transgenic mice which is consistent with my hypothesis. The tauKQ mouse model can assist in understanding the role of tau acetylation and tau progression for AD.

scholarly journals Doxycycline Interferes With Tau Aggregation and Reduces Its Neuronal Toxicity

2021 ◽  
Vol 13 ◽  
Author(s):  
Luciana Medina ◽  
Florencia González-Lizárraga ◽  
Antonio Dominguez-Meijide ◽  
Diego Ploper ◽  
Valeria Parrales ◽  
...  
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Dependent Manner ◽  
Free System ◽  
Neuronal Toxicity ◽  
A Cell ◽  
Disease Modifying ◽  
Time Required ◽  
Tau Aggregation ◽  
Dose Dependent

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

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