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

authored by

Kathrin Jahreis, Alina Brüge, Saskia Borsdorf, Franziska E. Müller, Weilun Sun, Shaobo Jia, Dong Min Kang, Nicolette Boesen, Seulgi Shin, Sungsu Lim, Anastasia Koroleva, Grzegorz Satała, Andrzej J. Bojarski, Elena Rakuša, Anne Fink, Gabriele Doblhammer-Reiter, Yun Kyung Kim, Alexander Dityatev, Evgeni Ponimaskin, Josephine Labus

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.

Organisation(s)

Nanoengineering

External Organisation(s)

Hannover Medical School (MHH)
German Center for Neurodegenerative Diseases (DZNE)
Korea Institute of Science and Technology
Korea University
University of Science and Technology UST
Instytut Chemii Bioorganicznej Polskiej Akademii Nauk
Otto-von-Guericke University Magdeburg
Center for Behavioral Brain Sciences (CBBS)

Type

Article

Journal

Alzheimer's and Dementia

Volume

19

Pages

5482-5497

No. of pages

16

ISSN

1552-5260

Publication date

12.2023

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Epidemiology, Health Policy, Developmental Neuroscience, Clinical Neurology, Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Psychiatry and Mental health

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1002/alz.13090 (Access: Open)