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Tau-targeting pharmacological strategies in neurodegenerative disease
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DOI：10.1016/j.tips.2026.07.008.png)
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Abstract
En 中文
Tau-directed therapeutics are moving beyond bulk protein reduction toward modalities that specifically target disease-relevant tau species. Small RNAs target tau mRNA; the focus is shifting from global tau suppression toward the specific modulation of distinct alternative splicing isoforms. Immunotherapies and chimeric degraders are both used to facilitate the degradation of tau protein, with emerging strategies now focused on augmenting their specificity for disease-associated tau proteoforms rather than broadly targeting total tau. Structure-based inhibitors are used to prevent tau aggregation while promoting disaggregation, but the seed-competent intermediates generated during disaggregation should be actively and promptly cleared to prevent cell-to-cell propagation. Novel chimeric constructs with distinct functionalities may be employed for either selective tau post-translational modification editing or cellular-level interventions; the latter encompasses targeted rescue and active clearance of neurofibrillary tangle-bearing cells.
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