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Hyperphosphorylation and aggregation of the microtubule‐associated protein tau cause the development of tauopathies, such as Alzheimer's disease and frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5‐HT7R) activity and pathological tau aggregation. Here, we evaluated 5‐HT7R inverse agonists as novel drugs in the treatment of tauopathies.

Based on structural homology, we screened multiple approved drugs for their inverse agonism toward 5‐HT7R. Therapeutic potential was validated using biochemical, pharmacological, microscopic, and behavioral approaches in different cellular models including tau aggregation cell line HEK293 tau bimolecular fluorescence complementation, primary mouse neurons, and human induced pluripotent stem cell–derived neurons carrying an FTD‐associated tau mutation as well …