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Review
. 2017 Oct 3;7(10):a024372.
doi: 10.1101/cshperspect.a024372.

The Prion-Like Behavior of Assembled Tau in Transgenic Mice

Florence Clavaguera  1 , Markus Tolnay  1 , Michel Goedert  2
Affiliations
Review

The Prion-Like Behavior of Assembled Tau in Transgenic Mice

Florence Clavaguera et al. Cold Spring Harb Perspect Med. .

Abstract

Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to spread from the neocortex to the brainstem. These findings implicate neuron-to-neuron propagation of tau aggregates. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here, we review recent findings that support prion-like mechanisms in the pathogenesis of tauopathies through the experimental use of transgenic mice.

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Figures

Figure 1.
Figure 1.
Induction and propagation of filamentous tauopathy in tau transgenic mouse models. (A) (Left) Mice expressing the 383 amino acid 4R human tau with the P301S mutation under the control of the murine Thy1 promoter develop abundant hyperphosphorylated (AT8-immunoreactive) and Gallyas–Braak silver-positive filamentous tau inclusions in various brain regions, including the brainstem, from which extracts were prepared for injection into the brains of ALZ17 mice. (Right) ALZ17 mice express the 441 amino acid 4R human tau isoform under the control of the murine Thy1 promoter. These mice show tau that is immunoreactive with the phosphorylation-dependent antibody AT8, but Gallyas–Braak silver negative, as shown here for the hippocampus. They also lack tau filaments. The sections were counterstained with hematoxylin. (B) Staining of the hippocampal CA3 region from 18-month-old ALZ17 mice with AT8, Gallyas–Braak silver and phosphorylation-dependent anti-tau antibody AT100, 15 months after no injection (upper panel) or after the injection with brain extract from 6-month-old P301S tau mice (lower panel). The injection of brain extracts induced the formation of AT100- and Gallyas–Braak silver-positive filamentous inclusions made of wild-type human tau. No such inclusions were found in ALZ17 mice injected with extracts from control mice (Clavaguera et al. 2009). The sections were counterstained with hematoxylin. (C) Spreading of filamentous tau pathology in ALZ17 mice injected with brainstem extracts from mice transgenic for human P301S tau. Gallyas–Braak silver staining of brain regions (subiculum, optic tract and thalamus, medial lemniscus) at a distance from the injection sites 15 months postinjection. The sections were counterstained with hematoxylin. Scale bars, 50 µm.
Figure 2.
Figure 2.
Prion-like properties of induced tau pathology. (A) 12-month-old heterozygous P301S tau mice 9 months after intraperitoneal (IP) or intracerebral (IC) injection with brainstem extracts from homozygous P301S tau mice. Gallyas–Braak silver-positive structures per cell nucleus (G/N ratios) in noninjected control mice (CO) and in IP- or IC-injected mice. Color maps representing average G/N ratios (CO, IP, and IC) of five sagittal brain sections per group. IP-injected mice had significantly higher G/N ratios in the brainstem and neocortex than CO mice. The major difference between IP- and IC-injected animals was located in the hippocampus, one of the two intracerebral injection sites. (B) Filamentous tau lesions formed in the brains of ALZ17 mice after injection of human brain extracts. Gallyas–Braak silver staining revealed NFTs after the injection of AD brain homogenates (left) and argyrophilic grains after the inoculation of AGD brain homogenate (middle). AT100 immunolabeling detected a tau-positive tufted-like astrocyte consecutive to the injection of AGD brain homogenate (right). The sections were counterstained with hematoxylin. Scale bars, 50 μm. (C) Induction of tau inclusions in nontransgenic C57Bl/6 mice 12 mo after intracerebral injection of brain homogenates from sporadic human tauopathies. Gallyas–Braak silver impregnation failed to detect tau filaments in noninjected mice (left) but revealed the presence of neuropil threads and coiled bodies in the dorsal thalamus following the injection of AD homogenate (middle). AT100 immunostaining of the hippocampal region showed the presence of a tufted-like astrocyte following the injection of AGD brain extract (right).
Figure 3.
Figure 3.
Possible mechanisms for tau-aggregate formation, intercellular transfer, and propagation. (1) Formation of tau filaments: For yet-unknown reasons, soluble wild-type tau (circle) can change its conformation (“misfolding”) (hexagon). It is also able to adopt abnormal conformations after contact with abnormally folded tau (templated misfolding). Generation of oligomers by nucleation is a slow phenomenon. However, once a nucleus has formed, the growth of aggregates is rapid. Moreover, fragmentation of aggregates provides new seeds and accelerates further aggregation. Tau filaments are at the end point of aggregation and consist of amyloid fibrils rich in β-sheet structure, which can adopt different conformations that may be responsible for the heterogeneity of tauopathies. These conformations may correspond to distinct strains of aggregated tau. A paired helical filament from an AD brain is shown (Crowther and Goedert 2000). Scale bar, 100 nm. (2) Interneuronal transfer: Tau may be released into the extracellular space in its soluble or misfolded form and/or be transported along the axon in both anterograde and retrograde directions. It may subsequently be taken up by neighboring cells, where tau filaments might induce aggregation of soluble tau in the cytoplasm. (3) Zoom on hypothetical mechanisms: Tau seeds circulate freely in the extracellular space or are contained in vesicles such as ectosomes or exosomes. They may penetrate neurons directly through the plasma membrane or by means of endocytosis. The transport of tau aggregates may also occur via nanotubes that connect the cytoplasm of adjoining cells.
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