Amisulpride as a potential disease‐modifying drug in the treatment of tauopathies

Abstract

INTRODUCTIONHyperphosphorylation 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.METHODSBased 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 as in two mouse models of tauopathy.RESULTSAntipsychotic drug amisulpride is a potent 5‐HT7R inverse agonist. Amisulpride ameliorated tau hyperphosphorylation and aggregation in vitro. It further reduced tau pathology and abrogated memory impairment in mice.DISCUSSIONAmisulpride may be a disease‐modifying drug for tauopathies.

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“…Serotonin (5-hydroxytryptamine, 5-HT) receptors are associated with both metabotropic and ionotropic function and fine-tuning cortical neuron behavior. Serotonin receptor activation has been linked to both amyloid-beta secretion and tau phosphorylation 38,39 . The lysosphingolipid cluster included lysophosphatidic acid receptors (Lpar) and metabotropic acetylcholine receptors.…”