Tau

What is Tau? Phosphorylated-tau? Hyperphosphorylated tau? Neurofibrillary Tangles?

Tau is a protein found in neurons in which its primary function, under normal physiological conditions, is to assist with maintaining structure, stabilizing microtubules and facilitating transport within the cell. While it is important to the function of a normal cell, tau is also associated with the pathology of several progressive diseases, referred to sometimes as tauopathies: Alzheimer's, corticobasal degeneration (CBD), dementia within parkinsonism-17 (FTDP-17), Pick disease (PiD), and progressive supranuclear palsy (PSP). Though it is the aggregation of hyperphosphorylated tau that is a hallmark of Alzheimer's.

Phosphorylated tau is a normal occurrence in the brain, especially during fetal development. After fetal development, concentrations return to a baseline. It is the hyperphosphorylation of tau that causes accumulations of tangles to form. 

Neurofibrillary tangles are characterized by an abnormal accumulation of hyperphosphorylated tau. When tau proteins become phosphorylated, they detach themselves from functioning microtubules and begin sticking to other tau proteins around them, disrupting cell function, communication and internal transportation. There are six different isoforms of tau that all self-assemble into either a paired helical filament (PHF) or a straight filament (SF). These filaments gather to arrange the NFT's that are a staple of Alzheimer's. 

Neurofibrillary Tangle Formation

The following experiment was conducted to explore if phosphorylated tau could self-assemble into PHFs and SFs, and, under what conditions this was able to be done. The researchers also questioned if the in vitro formation of these filaments were similar to those found is AD patients. In furthering their findings below, the researchers also explored under what physiological conditions (pH, temperature, ionic strength, concentration, etc.) were these filaments able to form. (Not addressed below)

Summary

There are several conclusions that can be drawn from the research above. Imaged by negative stain electron microscopy (NSEM), no filaments, neither PHFs nor SFs, were formed under conditions of induced dephosphorylation (fig. 1b). Filaments aggregated under conditions of induced deglycosylation and under the no-treatment condition as well (fig. 1c and fig. 1a respectively). Although, in the deglycosylation condition, 4nm protofilaments were most likely to dissociate from the main PHFs and SFs, resulting in an overall decreased ability to form filaments. These results confirmed the presupposition that AD phosphorylated tau is able to self-assemble into PHFs and phosphorylation and glycosylation are both necessary to this process. In addition to this, the self-assembly for these filaments in vitro resembled the same PHFs found in a patient's brain. Further investigation by the researchers indicated that all six different isoforms of tau were found in these filaments. 

Disruption of cell function and cell death are prominent features of Alzheimer's. A notable amount of cell death causes brain atrophy and brain region shrinkage in the later stages. It is important to know the mechanisms for this cascade of apoptosis and the interactions between the proteins involved. The reciprocal toxicity pictured in this feedback loop shows how phosphorylated tau is transformed into NFTs in the presence of βA. While the interdependence of these proteins is very unclear, it is noteworthy that their interaction can cause apoptosis through eventual damage to the mitochondria. From this figure, we can conclude that NFT formation and the presence of βA is in some way connected. Yet it also raises several other questions that have not yet been addressed in the library of data currently available:

• Can phosphorylated tau be formed in the absence of βA?

• Are there other proteins that can activate GSK-3β & CDK-5?

• Are there other natural or synthetic proteins that can take care of internal skeleton formation of neurons once tau loses its ability to?

• At what point in this feedback loop is it best to attempt an interjection to damage this relationship between tau and βA?

• Is there a threshold that the concentration of βA plaques reach before the acceleration of NFT formation begins?

These are the questions that will hopefully propel this field of research through the next couple decades. 

References 

Alonso, A. del C, et al. Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments. The National Academy of Sciences, 2001 June; 98(12). 6923-6928. doi: 10.1073pnas.121119298. 

Gao YL, et al. Tau in neurodegenerative disease. Ann Transl Med. 2018 May;6(10):175. doi: 10.21037/atm.2018.04.23. PMID: 29951497; PMCID: PMC5994507. 

Mishan, M. A., et al. (2019). Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases. Journal of Ophthalmic & Vision Research. 14. 491-505. 10.18502/jovr.v14i4.5459. 

U.S. Department of Health and Human Services. (2017, May 16). What Happens to the Brain in Alzheimer's Disease? National Institute on Aging. Retrieved March 22, 2023, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=Amyloid%20plaques,thought%20to%20be%20especially%20toxic 

Xia, Y., Prokop, S. & Giasson, B.I. “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegeneration 16, 37 (2021). doi: 10.1186/s13024-021-00460-5. 

Zhang H, et al. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease. Int J Biol Sci. 2021 May 27;17(9):2181-2192. doi: 10.7150/ijbs.57078.