Recent advances in cellular biosensor technology to investigate tau oligomerization

Lo, Chih Hung

doi:10.1002/btm2.10231

Cited by 14 publications

(15 citation statements)

References 133 publications

(440 reference statements)

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“…In spite of the evident key role of changes of tau phosphorylation and conformational status, assays monitoring these processes are still scarce (17). The conformational biosensors we developed here faithfully reported the conformational change of tau induced by phosphorylation or by MTs destabilization.…”

Section: Application Of Tau Interaction Biosensors For the Identifica...mentioning

confidence: 76%

“…The sensibility of our K18(P301L) interaction sensor is outstanding, spanning 4 logs of protein concentration of brain lysates and being able to discriminate between brain lysates from control and transgenic mice in as low as 300 pg of total protein after only 24h of incubation. Compared to existing FRET-based K18 aggregation sensors (14,17,50), the Nluc complementation-based Tau(P301L) and K18(P301L) interaction assays presented here are high-throughput compatible and require no further data integration following plate reading of the bioluminescence signal. We provide "proof-of-principle" evidence of the robustness of both assays and its application in the identification of small molecules able to interfere with tau seeding / self-interaction response, opening novel possibilities for the discovery of new drug candidates for tau-related neurodegenerative diseases.…”

Section: Application Of Tau Interaction Biosensors For the Identifica...mentioning

confidence: 99%

“…Despite significant improvements, the existing biosensors still have limitations either in terms of sensitivity (i.e. microscopy or western blot for visualization of small tau oligomers), of laborious data analysis (FRET-based assays), or of high-throughput screening compatibility (17). In order to develop improved tau biosensors for research and drug discovery application we used the recently developed highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) (18,19).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Cecon

Oishi

Luka

et al. 2023

eLife

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Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reports i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e. full-length or short fragments, wild-type, or the disease-associated tau(P301L) variant) further insights into the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.

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Section: Application Of Tau Interaction Biosensors For the Identifica...mentioning

confidence: 76%

Section: Application Of Tau Interaction Biosensors For the Identifica...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Cecon

Oishi

Luka

et al. 2023

eLife

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show abstract

“…Researchers are making a substantial effort to generate tau oligomers by purified recombinant protein strategies for studying oligomer conformations and their toxicity. Still, there is no specific toxic tau protein has been identified 35 . However, some cellular biosensor technology has been discovered to monitor the formation of tau oligomers and aggregates in the living cells 35 , e.g., fluorescence resonance energy transfer (FRET), bimolecular fluorescence complementation (BiFC), and split luciferase complementation (SLC).…”

Section: Resultsmentioning

confidence: 99%

Nonlocal Models in the Analysis of Brain Neurodegenerative Protein Dynamics with Application to Alzheimer's Disease

Pal¹,

Melnik²

2021

Preprint

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It is well known that today nearly one in six of the world's population has to deal with neurodegenerative disorders. While a number of medical devices have been developed for the detection, prevention, and treatments of such disorders, some fundamentals of the progression of associated diseases are in urgent need of further clarification. In this paper, we focus on Alzheimer's disease, where it is believed that the concentration changes in amyloid-beta and tau proteins play a central role in its onset and development. A multiscale model is proposed to analyze the propagation of these concentrations in the brain connectome. In particular, we consider a modified heterodimer model for the protein-protein interactions. Higher toxic concentrations of amyloid-beta and tau proteins destroy the brain cell. We have studied these propagations for the primary and secondary and their mixed tauopathy. We model the damage of a brain cell by the nonlocal contributions of these toxic loads present in the brain cells. With the help of rigorous analysis, we check the stability behaviour of the stationary points corresponding to the homogeneous system. After integrating the brain connectome data into the developed model, we see that the spreading patterns of the toxic concentrations for the whole brain are the same, but their concentrations are different in different regions. Also, the time to propagate the damage in each region of the brain connectome is different.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Cecon

Oishi

Luka

et al. 2022

Preprint

View full text Add to dashboard Cite

Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred as tauopathies, including Frontal Temporal Dementia and Alzheimer's disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably report i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e. full-length or short fragments, wild-type or the disease-associated tau(P301L) variant) further insights in the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors are aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.

show abstract

Recent advances in cellular biosensor technology to investigate tau oligomerization

Cited by 14 publications

References 133 publications

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Nonlocal Models in the Analysis of Brain Neurodegenerative Protein Dynamics with Application to Alzheimer's Disease

Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

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