Details
| Original language | English |
|---|---|
| Pages (from-to) | 5482-5497 |
| Number of pages | 16 |
| Journal | Alzheimer's and Dementia |
| Volume | 19 |
| Issue number | 12 |
| Early online date | 23 May 2023 |
| Publication status | Published - Dec 2023 |
Abstract
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.
Keywords
- amisulpride, antipsychotics, dementia, inverse agonists, serotonin receptor 5-HT7R, tau, tauopathies
ASJC Scopus subject areas
- Medicine(all)
- Epidemiology
- Medicine(all)
- Health Policy
- Neuroscience(all)
- Developmental Neuroscience
- Medicine(all)
- Clinical Neurology
- Medicine(all)
- Geriatrics and Gerontology
- Neuroscience(all)
- Cellular and Molecular Neuroscience
- Medicine(all)
- Psychiatry and Mental health
Sustainable Development Goals
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In: Alzheimer's and Dementia, Vol. 19, No. 12, 12.2023, p. 5482-5497.
Research output: Contribution to journal › Article › Research › peer review
}
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 -