TY - JOUR

T1 - Amisulpride as a potential disease-modifying drug in the treatment of tauopathies

AU - Jahreis, Kathrin

AU - Brüge, Alina

AU - Borsdorf, Saskia

AU - Müller, Franziska E.

AU - Sun, Weilun

AU - Jia, Shaobo

AU - Kang, Dong Min

AU - Boesen, Nicolette

AU - Shin, Seulgi

AU - Lim, Sungsu

AU - Koroleva, Anastasia

AU - Satała, Grzegorz

AU - Bojarski, Andrzej J.

AU - Rakuša, Elena

AU - Fink, Anne

AU - Doblhammer-Reiter, Gabriele

AU - Kim, Yun Kyung

AU - Dityatev, Alexander

AU - Ponimaskin, Evgeni

AU - Labus, Josephine

N1 - Funding Information: This work was supported by funds from Deutsche Forschungsgemeinschaft (DFG) through grant PO732, Excellence Cluster REBIRTH, and Alzheimer Forschung Initiative e.V. (AFI) #21043 to E.P., grant DI702/10‐1 to A.D. and through grant LA4465 to J.L. A.D. was supported by German Center for Neurodegenerative Diseases (DZNE) K.J. received the StrucMed‐Scholarship of the Hannover Biomedical Research School—Graduate School of Excellence and conducted the majority of her experimental contribution within the framework of this program. This research was also supported by the Korea Health Technology R&D Project (HU21C0223), the National Research Foundation of Korea (NRF) grant (2021R1A2C209373411 and 2022K2A9A2A2200008111) to Y.K.K., and the NRF grant (2022R1C1C100714611) to S.L.

PY - 2023/12

Y1 - 2023/12

N2 - INTRODUCTION: 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. METHODS: 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 as in two mouse models of tauopathy. RESULTS: Antipsychotic 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. DISCUSSION: Amisulpride may be a disease-modifying drug for tauopathies.

AB - INTRODUCTION: 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. METHODS: 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 as in two mouse models of tauopathy. RESULTS: Antipsychotic 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. DISCUSSION: Amisulpride may be a disease-modifying drug for tauopathies.

KW - amisulpride

KW - antipsychotics

KW - dementia

KW - inverse agonists

KW - serotonin receptor 5-HT7R

KW - tau

KW - tauopathies

UR - http://www.scopus.com/inward/record.url?scp=85159872589&partnerID=8YFLogxK

U2 - 10.1002/alz.13090

DO - 10.1002/alz.13090

M3 - Article

C2 - 37218673

AN - SCOPUS:85159872589

VL - 19

SP - 5482

EP - 5497

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 12

ER -