6 reasons to include tau oligomers in your R&D strategy for the treatment of Alzheimer’s Disease
As its name suggests, the microtubule-associated protein tau is known mainly for its role in stabilising the microtubules, thus contributing to maintenance of the axonal transport mechanisms essential to the survival of neurons. However, the physiological roles of tau are not limited to this function alone; tau is also involved in synaptic plasticity as well as in the regulation and protection of the genome . As we shall discuss in this article, changes in the functions of tau work together to set up the neurodegeneration mechanisms observed in tauopathies – specifically, they do so through the formation of tau oligomeric (TauO), which seems to be heavily enough involved in many pathological mechanisms to explain its “tau-xicity”.
Contents
- TauO is present in AD patients
- TauO leads to memory impairment
- TauO participates in the intracellular accumulation of tau
- TauO takes part in tau’s prion-like mechanisms
- TauO is the seed for the aggregates
- TauO destabilises nucleic acids
1. TauO is present in AD patients
Significant quantities of tau oligomers are present in patients with Alzheimer’s Disease (AD). TauO are found in the patients’ brains very early on (McInnes et al., 2018). From the early stages of Braak, TauO is detected in the frontal cortex, where neurofibrillary degeneration will occur at later stages of the disease (Maeda et al., 2006; Lasagna-Reeves et al., 2012). Moreover, the amount of TauO found in patients’ brains is predictive of the degree of cognitive impairment in AD patients (Lowe et al., 2018). TauO thus represents a potential new biomarker that could be used in the early diagnosis of AD (Sengupta et al., 2017). The presence of significant quantities of TauO in key areas from an early stage therefore makes it a prime target for new translational R&D research strategies.
2. TauO leads to memory impairment
Clinical data also show a correlation between the presence of tau and the intensity of cognitive deficits in patients. What impact does TauO have on the mechanisms underlying memory? Isolated from patient brains, TauO can cause a decrease in long term potentiation (LTP) in hippocampal cell cultures and slices of adult rat hippocampus (Lasagna-Reeves et al., 2011, 2012; Fá et al., 2016). TauO reduces phosphorilation of CREB, which in turn limits the acetylation of histones H3 and H4, necessary for LTP and spatial memory (Acquarone et al., 2019). Other mechanisms are also in play, since the effects of TauO also seem intimately linked to another actor in AD: the Amyloid Precursor Protein (APP). As the APP is involved in synapse stabilisation, its interaction with TauO could block APP activity, ultimately leading to the appearance of memory deficits in mice (Puzzo et al., 2017). These authors were able to show that only those wild-type mice expressing APP are sensitive to TauO, reporting alterations in LTP and memory functions.
Other TauO-induced cerebral dysfunctions have also been observed, particularly in relation to mitochondrial dysfunction and memory deficits. (Lasagna-Reeves et al., 2011; Shafiei et al., 2017; Zheng et al., 2020).
3. TauO participates in the intracellular accumulation of tau
One of the two historical biomarkers of AD is the presence of neurofibrillary degeneration linked to the accumulation of tau in the intracellular compartment. Here again, TauO seems to play a key role. Tau acetylation, favouring its oligomerisation, is enough to induce both cognitive disorders and a reduction in the number of synapses in mice(Maeda et al., 2006; Lasagna-Reeves et al., 2011, 2012). By limiting interactions between tau lysine residues and the ubiquitin/proteasome system, this acetylation also favours the accumulation of tau at intracellular level (Min et al., 2010).
In the same way, TauO is also able to limit the activity of the endosome-lysosome/autophagy system (Chen et al., 2020).
4. TauO takes part in tau’s prion-like mechanisms
TauO could also support tau’s prion-like behaviour. Several in vitro studies have shown that the use of human TauO is capable of gradually contaminating neurons.
Further, in vivo studies have shown that intracerebral administration of purified tau protein from the brains of AD patients leads to the formation of numerous tau inclusions in non-transgenic mice (Guo et al., 2016). The results of this study are complemented by other studies showing that TauO is essential to the propagation of tau in vivo (Lasagna-Reeves et al., 2012; Usenovic et al., 2015).
The cell types and mechanisms involved have yet to be clearly identified. Nevertheless, recent work has investigated various possible mechanisms supporting the spread of tau. The acetylation of tau seems to contribute to cell-to-cell propagation in the brain (Tai et al., 2014). A 2020 study has shown that Heparan Sulphate Proteoglycan (HSPG) is involved in the internalisation of TauO. Moreover, this mechanism is reversible through the use of HSPG antagonists, which reduce TauO internalisation, limit translocation in the endosome-lysosome/autophagy system and ultimately reduce the appearance of tau in fibrillar form at intracellular level (Puangmalai et al., 2020).
5. TauO is the seed for the aggregates
Tau aggregate formation is clearly related to a change in monomer conformation.
Monomeric tau has a core (microtubule binding domaine (MBD)) that is positively charged, thus allowing interaction with the negatively charged tubulin and preventing it from interacting with other tau monomers. In pathological conditions (for example, when tau is strongly phosphorylated) positive charges are neutralised by the phosphorus groups, which has a two-fold effect: tau monomer can no longer interact with the tubulin and becomes detached – that is, the protein loses its microtubule stabilising function, and the change in configuration of tau monomer allows it to assemble with other monomers to form oligomers (Morris et al., 2011).
This same phenomenon of change in the configuration of the tau monomer can be observed in the presence of other charged compounds such as RNA, heparin or micelles (Goedert et al., 1996; Kampers et al., 1996; Chirita et al., 2003).
Figure 1: Change to tau monomer configuration and formation of TauO
The precise mechanisms of tau toxicity are not yet known, but seem to be linked to tau’s three-dimensional conformation. In “paper-clip” physiological condition of tau, the N-terminal end will be close to the MBD. In pathological conditions, the “paper-clip” would be open, allowing activation of the phosphatase-activating domain, and thus causing intracellular disturbances (Kanaan et al., 2016).
6. TauO destabilises nucleic acids
One lesser-known role of tau is the one it plays at cell nucleus level, which is equally crucial to the survival of neurons. Yet tau aggregates have been found in the cell nucleus of brain tissue of AD patients.
In both animals and humans, in vitro and in vivo studies show that non-pathological forms of the tau protein participate in the protection of DNA integrity and in the metabolism of nuclear and cytoplasmic RNA (Violet et al., 2015; Mansuroglu et al., 2016; Sotiropoulos et al., 2017). The interaction of tau and DDX6 favours increased activity among the mi-RNAs participating in the regulation of mRNAs. (Chauderlier et al., 2018). Conversely, the presence of pathological forms such as TauO disrupts these core protection mechanisms (Mansuroglu et al., 2016; Sotiropoulos et al., 2017; Montalbano et al., 2020). In addition to the loss of protective and regulatory functions, TauO also gains toxic biological functions by disrupting trafficking through nuclear pores via interaction with Nup98 (Eftekharzadeh et al., 2018). An interaction with a protein called TIA1, which belongs to the family of RNA binding proteins, increases TauO stability and thus builds their toxicity.
This has been a quick overview of some of the abundant current literature on Tau, which is unanimous: TauO could be key to understanding AD and seems a relevant target. If you’d like to integrate TauO to your research projects, please get in touch!
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