Tauopathies are a type of type of neurodegenerative disease which get their name from the accumulation of Tau protein that occurs in all of them; these diseases include Alzhiemer’s disease (AD), Pick’s disease, progressive supranuclear palsy, and post-encephalitic parkinsonism, and more. Although there has been a concerted effort to better understand and treat Tau protein aggregation, all tau-targeting therapeutics developed so far have failed. This lack of discovery in the field suggests a better approach is needed to understand Tau protein. In a recent paper, Giong, Subramanian, Yu & Lee (2021) make the case for non-rodent models as a way forwards.
Figure 1. A healthy neuron and a pathological neuron in tauopathy. In a healthy neuron, Tau is usually found in axons but also located in dendrites, the nucleus, the plasma membrane and synapses. In the tauopathy condition, Tau undergoes PTMs such as hyperphosphorylation, resulting in the detachment from microtubules and the formation of aggregates. Tau dysfunction causes many neurodegenerative phenotypes such as pre- and postsynaptic decays, axonal degeneration, and eventually neuronal death (Giong et al., 2021; Lieff, 2015))
The Tau protein was discovered nearly fifty years ago, and has become increasingly researched in the years since (Giong et al., 2021). In fact, Tau is now one of the most well-known aspects of the central nervous system (CNS) thanks to its association with Alzheimer’s Disease. While Tau normally functions to maintain the stability of microtubules, in Alzheimer’s Disease, a misfolding of the protein occurs which results in a build-up of the Tau protein. This build-up is one of two defining features of Alzheimer’s: the other is the accumulation of Amyloid-β plaques. These features engage in a negative feedback loop in which they drive each other into a toxic state and ultimately, drive healthy neurons to disease [Figure 2] (Bloom, 2014). Tau protein malfunction is not only found in Alzheimer’s, however, but is a widely found phenomenon in a group of neurodegenerative diseases that have been categorized as ‘Tauopathies’.
Figure 2. A) Healthy neuron vs. neuron with misfolding Tau protein. B) Healthy brain vs. AD brain showing effects of Tau protein malfunction ((Giong et al., 2021; Jonlieff, 2015)
Another well-known Tauopathy is Chronic Traumatic Encephalopathy (CTE), which became part of the public consciousness thanks to news coverage of numerous professional football players developing the neurodegenerative condition after retirement. Since CTE is caused by repetitive mild traumatic brain injury (TBI), players of contact sports such as football, boxing, and rugby are particularly at risk ((Tauopathies, n.d.). Like in Alzheimer’s, brains with CTE show a significant aggregation of Tau protein. While this led researchers to initially think that CTE led to Alzheimer’s, it has been found that there is a distinctive pattern to the build-up of Tau proteins in CTE compared to Alzheimer’s [Figure 3] (Katsumoto et al., 2019).
Figure 3. Left to right: brain PET scans of healthy control, former NFL player with suspected CTE, and person with Alzheimer’s Disease. Areas with highest levels of abnormal Tau protein appear red/yellow, medium levels appear green, and lowest levels appear blue (Small et al., 2013).
Despite being known for decades, there has yet to be a successful development of a Tau-target therapeutic compound. Historically, mice models have been used most commonly to study Tau malfunction, yet with the pressing and ever growing need to better understand tau malfunction in order to develop treatments, researchers are beginning to shift away from mice. Instead, researchers are utilizing cheaper, and highly genetically amenable animal models, such as flies (Drosophila), zebrafish, and C. elegans (Giong et al., 2021). In humans, the Tau protein consists of six isoforms translated from alternatively spliced mRNAs of a single microtubule-associated protein Tau gene (MAPT) containing 16 exons, and so, mutations of this gene can be used to create these non-mammalian models of Tauopathy. In a previous article we discussed the advantages and limitations of Drosophila, zebrafish, and C. elegans as neurodegenerative models, but below we will expand upon that, looking specifically at these model organisms in relation to Tau protein research [Figure 4].
Figure 4. Summary of strengths and limitations for mousem, Drosophila, zebrafish & C. elegans Tauopathy models ((Giong et al., 2021; Lieff, 2015)).
Drosophila Model of Tauopathy
Nearly 100 Drosophila Tau models have been created, and while most of them do not show tau aggregation, many tauopathy-related phenotypes appear in these models. The ability for these phenotypes to be observed and recorded easily makes the Drosophila particularly useful in large-scale screens (Giong et al., 2021).
The most prominent limitation for using a Drosophila Tauopathy model, is that the Drosophila has relatively simple brain connectivity and its structure is different from the human brain. Thus, studies utilizing Drosophila are more limited in their translatability than studies which use other vertebrate species.
Zebrafish Model of Tauopathy
Zebrafish are advantageous as a tauopathy model for several reasons, but perhaps most notably, they offer a vertebrate, high-throughput screening model that is easily screened during both their larval and adult stages.
Currently, there are fewer zebrafish tauopathy models than mouse, drosophila, or C. elegans models. . However, more models are expected to be created since the existing models have proven promising: for instance, a model which overexpressed the human Tau variant Tau A152T confirmed it as a risk factor for FTD and Alzheimer’s Disease (Lopez et al., 2017).
C. elegans Model of Tauopathy
Like the previously mentioned models, C. elegans is a tauopathy model that is capable of large-scale genetic screening, but it stands apart from other models in just how convenient it is as a model. In fact, C. elegans’ phenotypes can be assessed faster than any other model organism. In Tau protein research specifically, C. elegans have proven themselves to be such valuable models that it has been suggested they become part of the therapeutic development pipeline as a proof-of-hypothesis step before moving into higher model systems and clinical trials (Giong et al. 2021).
This being said, with their simplistic structure and small size, C. elegans‘ advantages are also its limitations, and make it unable to completely replace vertebrate models.
While mammalian models have primarily been used in Tauopathy research, there have been significant advances in understanding the complexities of Tau malfunction using non-mammalian models such as Drosophila, zebrafish, and C. elegans. These alternative models have provided a way forwards for Tau research, which could be crucial for this currently difficult to research, and incurable, group of diseases.
Figure 5. Comparisons of the strength and limitations of Drosophila, zebrafish, and C. elegans as tauopathy models. The evaluated criteria (“Features”) are represented as the thicker means the better. For example, in the Low cost feature, C. elegans stands in the first place which is the cheapest, followed by Drosophila in the second and zebrafish in the last.
- Bloom, G. S. (2014). Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurology, 71(4). https://doi.org/10.1001/jamaneurol.2013.5847
- Giong, H.-K., Subramanian, M., Yu, K., & Lee, J.-S. (2021). Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models. International Journal of Molecular Sciences, 22(16), 8465.
- jonlieff. (2015, December 28). The Role of Tau in Brain Function and Dementia. https://jonlieffmd.com/blog/human-brain/the-role-of-tau-in-brain-function-and-dementia
- Katsumoto, A., Takeuchi, H., & Tanaka, F. (2019). Tau Pathology in Chronic Traumatic Encephalopathy and Alzheimer’s Disease: Similarities and Differences. Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.00980
- Lopez, A., Lee, S. E., Wojta, K., Ramos, E. M., Klein, E., Chen, J., Boxer, A. L., Gorno-Tempini, M. L., Geschwind, D. H., Schlotawa, L., Ogryzko, N. V., Bigio, E. H., Rogalski, E., Weintraub, S., Mesulam, M. M., Tauopathy Genetics Consortium, Fleming, A., Coppola, G., Miller, B. L., & Rubinsztein, D. C. (2017). A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain: A Journal of Neurology, 140(4), 1128-1146.
- Small, G. W., Kepe, V., Siddarth, P., Ercoli, L. M., Merrill, D. A., Donoghue, N., Bookheimer, S. Y., Martinez, J., Omalu, B., Bailes, J., & Barrio, J. R. (2013). PET scanning of brain tau in retired national football league players: preliminary findings. The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry, 21(2). https://doi.org/10.1016/j.jagp.2012.11.019
- Tauopathies. (n.d.). Retrieved October 5, 2021, from https://ind.ucsf.edu/research/tauopathies