New Insights Into Drug Discovery Targeting Tau Protein

Abstract

Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

Keywords: aggregation; immunotherapy; inflammation; liquid-liquid phase separation; microtubule stabilizer; oligonucleotide therapy; post-translational modifications; tau protein.

Figure 1

Mechanism of tau-targeted drugs in clinical trials. In tauopathies, tau protein is dissociated from microtubules by post-translational modifications, including phosphorylation, and tau is mis-sorted into the somatodendritic compartment. The mis-sorted tau undergoes further post-translational modifications and is converted to misfolded tau. After tau self-assembly, tau filaments are formed via tau oligomers. The pathological tau seed is subsequently released from the pre-synapse and propagated into post-synapses. Tau-based drugs in clinical trials are inhibitors of post-translational modification (Figure 2) or tau aggregation inhibitors (Figure 3), as well as oligonucleotides to reduce tau expression, microtubule stabilizers, and immunotherapeutics.

Figure 2

Mechanism of tau post-translational modification inhibitors in clinical trials. Post-translational modifications, including phosphorylation and acetylation, regulate the binding of tau to microtubules. Microtubule instability and depolymerization are observed in tauopathies, suggesting a therapeutic role for microtubule stabilizers. Phosphorylation, acetylation, or both, enhance tau aggregation. O-GlcNAcylation at serine and threonine compete with phosphorylation of the same residues. Tau degradation is inhibited by acetylation. The post-translational modifications are tightly regulated by various enzymes that mediate the addition and removal of the modifying groups. In clinical trials, tau kinase inhibitors or P300 acetyltransferase inhibitors have been investigated for their ability to inhibit tau phosphorylation or tau acetylation. The usefulness of O-GlcNAcase inhibitors to elevate tau O-GlcNAcylation has also been examined in clinical trials. Ac, acetylation; Gly, O-GlcNAcylation; P, phosphorylation.

Figure 3

Processes of tau aggregation. Hyperphosphorylated tau is detached from microtubules and mislocalized in the somatodendritic compartment of neurons. In vitro studies have shown that tau is self-assembled to form tau oligomers and granular tau oligomers before forming NFTs. Tau aggregation inhibitors that halt these processes may be useful in the treatment of tauopathies.

Figure 4

Tau droplet formation by liquid-liquid phase separation (LLPS) is a key initial step in aberrant tau aggregation. Tau must be abundant before it begins to aggregate. LLPS-mediated formation of droplets supersaturated with tau may be a key step in the latter process. A droplet is a reversible structure formed by weak interactions, suggesting that tau droplets may be a better drug target than irreversible tau aggregation.