Therapeutic strategies for tauopathies and drug repurposing as a potential approach

Abstract

Tauopathies are neurodegenerative diseases characterized by the deposition of abnormal tau in the brain. To date, there are no disease-modifying therapies approved by the U.S. Food and Drug Administration (US FDA) for the treatment of tauopathies. In the past decades, extensive efforts have been provided to develop disease-modifying therapies to treat tauopathies. Specifically, exploring existing drugs with the intent of repurposing for the treatment of tauopathies affords a reasonable alternative to discover potent drugs for treating these formidable diseases. Drug repurposing will not only reduce formulation and development stage effort and cost but will also take a key advantage of the established toxicological studies, which is one of the main causes of clinical trial failure of new molecules. In this review, we provide an overview of the current treatment strategies for tauopathies and the recent progress in drug repurposing as an alternative approach to treat tauopathies.

Keywords: Alzheimer's disease (AD), Neurofibrillary tangles (NFTs); Microtubule (MT); Phosphorylated tau (p-tau); Post-translational modifications (PTMs); Repurposing; Tau; Tauopathy.

Fig. 1.

Schematic representation of full-length tau (2N4R) and five isoforms. The repeat regions contain two hexapeptide motifs (²⁷⁵VQIINK²⁸⁰ in R2, ³⁰⁶VQIVYK³¹¹ in R3) with higher tendencies to form β-sheet [21,22]. Because of the alternate splicing of MAPT gene, six different isoforms of tau protein are formed. N2 is missing in 1N4R; both N1 and N2 are missing in 0N4R; R2 is missing in 2N3R; N2 and R2 are missing in 1N3R; N1, N2, and R2 are missing in 0N3R [23].

Fig. 2.

Summary of the aggregation process of tau to form neurofibrillary tangles. (a) Binding of tau on the surface of MT enhances the stability of MT. (b) Post-translational modifications (PTMs) can disengage tau from MT. (c) External or internal factors, e.g., polyanions or acidic cofactor such as RNA and lipid membranes or repeat fragments, help the fibrillation process through the nucleation of oligomers and NFT formation via PHF and SF (d) [,–44,49,50,64,282].

Fig. 3.

Examples of potential drug candidates for the treatment of tauopathies by modification of tau aggregation process.

Fig. 4.

(a) Schematic representation of the function of drug molecules to bind to MT and act as MT stabilizers. (b) Examples of newly developed MT stabilizers. (c) Examples of drugs with repurposing potential to stabilize MT.

Fig. 5.

Examples of drugs with repurposing potential for the treatment of tauopathies by modification of tau aggregation process.