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

verfasst von

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.

Organisationseinheit(en)

Nanoengineering

Externe Organisation(en)

Medizinische Hochschule Hannover (MHH)
Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE)
Korea Institute of Science and Technology
Korea University
University of Science and Technology UST
Instytut Chemii Bioorganicznej Polskiej Akademii Nauk
Otto-von-Guericke-Universität Magdeburg
Zentrum für Neurowissenschaftliche Forschung (CBBS)

Typ

Artikel

Journal

Alzheimer's and Dementia

Band

19

Seiten

5482-5497

Anzahl der Seiten

16

ISSN

1552-5260

Publikationsdatum

12.2023

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Epidemiologie, Health policy, Entwicklungsneurowissenschaften, Klinische Neurologie, Geriatrie und Gerontologie, Zelluläre und Molekulare Neurowissenschaften, Psychiatrie und psychische Gesundheit

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1002/alz.13090 (Zugang: Offen)