Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?
Abstract
:1. Introduction
2. Tau Structure and Processing
3. The “Prion-like” Nature of Tau and Its Strains
4. Principal Approaches in the Rodent Model’s Scenery for Tau Pathology
5. Cellular Models of Tau Pathology: Aggregation, Seeding, and Spreading
5.1. In Vitro Modelling of Tau Aggregation: Seminal Models
5.2. Cellular Models of Tau Seeding: Cellular Internalization of Proteopathic Tau Seeds
Cell-Based Assays: Proteopathic Seeding
5.3. Cellular Models of Tau Spreading and Serial Propagation
5.4. Tauopathies in Primary Neural Cells: The Use of Microfluidic Devices in Experimental Design
5.5. iPSCs for Modeling and Studying Tauopathies In Vitro
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Tau Isoform | Variants | Host Cell | Expression | Aggregation Inducer | Detection Method | Reference |
---|---|---|---|---|---|---|
4RD | Wild-type ΔK280 ΔK280/PP (I277P/I308P) | N2a | Stable doxycycline-inducible | Spontaneous formation | ThS ICC | [83] |
2N4R | Wild-type | HEK293 | Stable doxycycline-inducible | Congo red | ICC | [84] |
0N4R Tau1-421 | Wild-type | HEK293 | Transient expression | Spontaneous formation Phosphorylation | FRET (CFP/YFP) | [85] |
0N4R 4RD | ΔK280 I277P/I308P | HEK293 | Transient expression | Spontaneous formation Phosphorylation | BiFC (Split GFP) | [93] |
2N4R | Wild-Type | HEK293 | Stable expression | Phosphorylation | BiFC (Split Venus) | [94] |
Tau Isoform | Variants | Host Cell | Expression | Extracellular Tau | Detection Method | Reference |
---|---|---|---|---|---|---|
4RD Tau40 | Wild-type | HEK293 C17.2 | Transient expression | Tau PFFs | YFP ICC | [20] |
1N3R 1N4R | Wild-type | SH-SY5Y | Transient expression | Tau PFFs | GFP ICC | [102] |
3RD 4RD | L226V/V337M P301L/V337M | HEK293 | Transient expression | Crude brain homogenates from human AD, PiD, CTE, AGD, CBD, and PSP patients | YFP | [103] |
Tau40 | Wild-type ΔK280 P301L R406W | QBI-293 | Transient expression | Tau PFFs | ICC | [77] |
Tau40 | P301L | QBI-293 | Stable doxycycline-inducible | Tau PFFs | GFP ICC | [91,104] |
4RD | P301S | HEK293 | Stable expression | -Tau PFFs -Tau assemblies purified from AD patients | SLC (NLuc/CLuc) | [49] |
4RD | P301S | HEK293 | Stable expression | -Tau PFFs -AD brain lysate -P301S brain lysate | FRET (CFP/YFP) | [96] |
4RD | P301S | HEK293 | Stable expression | -Tau PFFs -AD brain lysate -AD CSF | FRET (Clo/Cler) | [98] |
4RD | ΔK280 P301L/V337M ΔK280/I22P /I308P | HEK293 | Transient expression | Tau PFFs | FRET (CFP/YFP) Antibody | [95] |
Model | Cell Source | Type of Tau Seed | Detection Method | Reference |
---|---|---|---|---|
2D | Neurons derived from wild-type hiPSCs with two MAPT mutations | K18 fibrils (P301L) | AlphaLISA | [135] |
2D | Wild-type hiPSC- neurons | Full-length human tau monomer and oligomer seeds | ICC ThS | [82] |
2D | Familial AD patient hiPSC- neurons expressing a tau aggregation biosensor | Tau seeds derived from mice carrying the MAPT P301L mutation (rTg4510) | in vitro longitudinal single-cell live-imaging system | [81] |
2D | -MAPT-wild-type hiPSC- neurons -MAPT-P301S/E10 + 16 hiPSC-neurons | -Sarkosyl-insoluble material from AD brains -Sarkosyl-insoluble material from healthy control brains | ICC HTRF | [136] |
3D (cerebral organoid) | -Wild-type hiPSC-neurons -Familial AD patient hiPSC-neurons | Spontaneous formation | ICC | [80] |
3D (cells in Matrigel) | ReNcell human neural stem cells with familial AD mutations APPSL and PS1ΔE9 | Spontaneous formation | ICC Modified Gallyas silver staining | [137] |
3D (cerebral organoids) | -Wild-type hiPSC-neurons -Familial AD patient hiPSC-neurons | Spontaneous formation | ICC ThS | [138] |
Model | Advantages | Disadvantages |
---|---|---|
In vivo: rodent models of tauopathies | Transgenic models reproduce many of the tau pathologies seen in the brains of human patients | Most transgenic models do not entirely mimic the hallmarks of sporadic human tauopathies in terms of the morphology of tau aggregates and the affected cell types |
The overexpression of mutated forms results in a rapid and robust tau pathology | Most transgenic models rely on the overexpression of mutant tau in virtually all brain cells, making tau spreading studies nearly impossible | |
Allow for the evaluation of behavioral impairments | Time consuming and expensive | |
Inoculation models of patient-derived material are highly translationally relevant models as they allow the investigation of tau spreading | Not suitable for high-throughput approaches | |
They include the complexity of the nervous system, improving their translational value compared to other models | Difficult to monitor tau aggregation and spreading with high spatiotemporal resolution | |
2D mammalian immortalized cell lines | Rapid experimental turnaround time | Most models do not reproduce neuronal phenotypes |
Easy to culture and transfect | Models that partially differentiate to neuronal phenotypes (i.e., SH-SY5Y) are cancer-derived cells | |
Labeling techniques are easily introduced to monitor and track aggregate formation with spatiotemporal resolution | Most models are not complex enough to produce transnationally relevant results regarding tau spreading | |
Excellent platforms for high-throughput approaches such as drug screening, especially in monoclonal cell lines | They do not reproduce the complexity of the nervous system | |
Microfluidic devices: murine neural cells | Excellent platforms for the study of tau spreading as they allow to track the movement of tau aggregates across synapses | Laborious to prepare and maintain |
Ideal platform for spatiotemporal separation of neuronal populations, allowing neural network modeling | High levels of variability between independent experiments (e.g., different litters) | |
Small reaction volumes needed | Difficult to transfect | |
2D iPSC-derived neurons | Maintain the genetic information of donors and can replicate the disease phenotype of the donor in vitro | Lack of complexity |
Easily gene-edited to express tau mutations | Neuronal immaturity | |
Tau seeds can be easily introduced to the culture | In vitro differentiation induced heterogeneity | |
Labeling techniques are easily introduced to monitor and track aggregate formation with spatiotemporal resolution | Labor- and time-intensive generation and characterization | |
Excellent platforms for high-throughput approaches such as drug screening | Lack of intercellular communication between different cell types | |
3D Cerebral organoids | Maintain the genetic information of donors | Highly variable culture protocols, which can lead to varying outcomes between groups |
Can replicate the disease phenotype without genetic manipulation i.e., spontaneous tau phosphorylation/aggregation | Lack of vasculature | |
Closely recapitulate the laminar organization of the developing human cortex and thus can model tau spreading in a more physiologically relevant manner | High variability of tau expression between organoids | |
Allow for interactions between different neural cell types | Oligodendrocytes and microglia are often not well formed | |
Viable for much longer than neural cells in 2D-culture, allowing the study of long-term effects of tau pathology | More difficult to monitor and track aggregate formation with spatiotemporal resolution due to the dense 3D tissue | |
Capable of mimicking perfusion and diffusion-based molecular transport | Can develop a necrotic core caused by lack of oxygen and nutrient diffusion into the inner-most layers | |
Can be used to study endolysosomal trafficking abnormalities that affect tau pathology | Labor- and time-intensive generation and characterization |
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Sala-Jarque, J.; Zimkowska, K.; Ávila, J.; Ferrer, I.; del Río, J.A. Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays? Int. J. Mol. Sci. 2022, 23, 11527. https://doi.org/10.3390/ijms231911527
Sala-Jarque J, Zimkowska K, Ávila J, Ferrer I, del Río JA. Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays? International Journal of Molecular Sciences. 2022; 23(19):11527. https://doi.org/10.3390/ijms231911527
Chicago/Turabian StyleSala-Jarque, Julia, Karolina Zimkowska, Jesús Ávila, Isidro Ferrer, and José Antonio del Río. 2022. "Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?" International Journal of Molecular Sciences 23, no. 19: 11527. https://doi.org/10.3390/ijms231911527