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Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays? - PubMed

  • ️Sat Jan 01 2022

Review

Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?

Julia Sala-Jarque et al. Int J Mol Sci. 2022.

Abstract

Tauopathies are a group of neurodegenerative diseases characterized by the hyperphosphorylation and deposition of tau proteins in the brain. In Alzheimer's disease, and other related tauopathies, the pattern of tau deposition follows a stereotypical progression between anatomically connected brain regions. Increasing evidence suggests that tau behaves in a "prion-like" manner, and that seeding and spreading of pathological tau drive progressive neurodegeneration. Although several advances have been made in recent years, the exact cellular and molecular mechanisms involved remain largely unknown. Since there are no effective therapies for any tauopathy, there is a growing need for reliable experimental models that would provide us with better knowledge and understanding of their etiology and identify novel molecular targets. In this review, we will summarize the development of cellular models for modeling tau pathology. We will discuss their different applications and contributions to our current understanding of the "prion-like" nature of pathological tau.

Keywords: neurodegeneration; seeding; spreading; tauopathies.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Schematic representation of tau isoforms. In the adult human brain, tau is found as six major isoforms (352-441 amino acids) resulting from alternative mRNA splicing. The N-terminal domain consists of either 0, 1, or 2 inserts encoded by exons 2 and 3 (0N, 1N, or 2N). The proline-rich domain is followed by the repeat domain (RD) also known as the microtubule binding domain (MTBR). Here, inclusion of exon 10 produces tau isoforms with four repeats (4R), whereas its exclusion produces isoforms with three repeats (3R). The RD is followed by the C-terminal domain.

Figure 2
Figure 2

Schematic diagram of cell-to-cell progression of tau pathology. j The formation of tau aggregates begins in a donor neuron (pink) when a misfolded seed-competent tau (red) templates its misfolded state to its endogenous monomeric counterpart (blue), through a process known as seeding. Ultimately, the seeding process produces tau aggregates with amyloid properties. In parallel, tau seeds travel along the axon to the synaptic terminal of the donor neuron. k Once there, tau is released or transferred from the donor neuron to the receptor neuron (greenish-blue). Although not depicted here, glial cells could also internalize misfolded tau seeds. l Next, the receptor neuron internalizes seeded-competent tau. This diagram depicts only one of the several proposed mechanisms related to trans-cellular spreading, in which free tau seeds are released from the axon terminal and are internalized by the receptor neuron through direct membrane fusion. However, numerous studies have proposed a variety of cellular pathways involved in the progression of pathological tau, as reviewed by in steps k and l [46,47,48]. The exact nature of the pathological tau involved in the cell-to-cell transfer process is also unknown, and different groups have proposed a variety of candidates [49,50,51]. m Inside the receptor neuron, pathogenic tau can recruit endogenous cellular tau and seed further tau aggregation. Overall, this process ensures the progression of the pathology.

Figure 3
Figure 3

Schematic representation of the most commonly used microfluidic platforms for modeling tau spreading. All these models allow for the isolation of soma/axons, along with treating each channel independently. (A) schematic representation of the two-chambered model [79] shows the architecture of the microfluidic device. Neural cells are seeded in the soma compartment (orange). After several, only the axons have been able to grow and reach the axonal compartment (green); (B) schematic representation of the three-chambered model that allows for the co-culture of two populations of primary neurons [119]. Here, the third chamber (blue) is used to seed the second population; (C) schematic representation of the three-chambered model to co-culture three independent neural populations [78].

Figure 4
Figure 4

iPSCs-based 2D and 3D approaches for modelling tauopathies in vitro. Somatic cells, such as fibroblasts, can be taken from patients with either a tauopathy or healthy controls, and be reprogrammed to iPSCs, which can subsequently be differentiated into various types of neurons. Both 2D and 3D approaches have been studied to model different types of tauopathies. Studies utilizing these two models have successfully shown the formation of tau aggregates along with neurodegeneration. 2D neuron cultures have also been used to examine the mechanisms behind tau seeding and spreading. However, 2D cultures lack the intricate microenvironment and structural arrangement of the human brain. 3D brain organoids are comprised of a variety of different neuronal cell types, including neurons, neural progenitors, oligodendrocytes, and astrocytes, which organize into an anatomically-specific structure that closely mimics that of the developing human brain. This model allows for examining the interactions between different neuronal cell types, which better models the processes that occur in vivo compared to 2D models. The continued improvement of these iPSC-based technologies will contribute to a better understanding of the pathological mechanisms involved in tauopathies and will hopefully lead to the development and discovery of effective treatments against them.

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