Therapeutic Targeting of Tauopathies: From Druggable Biology to Precision Intervention.

Abstract

Tauopathies encompass a heterogeneous group of neurodegenerative disorders characterized by the transition of tau from a microtubule-stabilizing protein into pathogenic, seed-competent species. Increasing evidence has redefined tau from a descriptive pathological hallmark to a pharmacologically actionable target across multiple disease stages. Therapeutic opportunities are now emerging across several interconnected modules, including microtubule-associated protein tau (MAPT) gene dysregulation, 3-repeat:4-repeat (3R:4R) tau imbalance and pathogenic post-translational modification (PTM). Additional modules involve aggregation and seeding, liquid-liquid phase separation (LLPS), prion-like propagation, co-pathological protein interactions, and downstream injury. At the nucleic acid level, antisense oligonucleotides and splice-correcting strategies reduce total tau expression or restore pathogenic isoform balance. At the protein level, active and passive immunotherapies, proteolysis-targeting chimera (PROTAC)-based degradation, and autophagy-enhancing approaches aim to lower tau burden or eliminate pathological species. PTM-directed strategies target the transition from microtubule-bound tau to toxic soluble intermediates. However, clinical translation remains constrained by limited specificity and incomplete functional benefit. Aggregation and seeding have emerged as pharmacologically tractable processes. Key targets include the amyloidogenic motifs paired helical filament 6 (PHF6; 306-311, VQIVYK) and PHF6* (275-280, VQIINK). In parallel, LLPS and tau propagation represent additional therapeutic cascades. These involve condensate maturation, seed release, cellular uptake, glial processing, glymphatic clearance. Beyond tau-centered approaches, increasing attention has also turned to amyloid-β (Aβ) and α-synuclein co-pathology. Adjunct strategies are being developed to target neuroinflammation, synaptic dysfunction, microtubule destabilization and mitochondrial stress. Collectively, current evidence supports a paradigm shift from broad pan-tau intervention toward stage-specific, species-specific, and combination-based therapeutic strategies.