Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Dec;19(12):5482-5497.
doi: 10.1002/alz.13090. Epub 2023 May 23.

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

Kathrin Jahreis  1 , Alina Brüge  1 , Saskia Borsdorf  1 , Franziska E Müller  1 , Weilun Sun  2 , Shaobo Jia  2 , Dong Min Kang  3   4 , Nicolette Boesen  3   5 , Seulgi Shin  3 , Sungsu Lim  3 , Anastasia Koroleva  6 , Grzegorz Satała  7 , Andrzej J Bojarski  7 , Elena Rakuša  8 , Anne Fink  8 , Gabriele Doblhammer-Reiter  8 , Yun Kyung Kim  3   7 , Alexander Dityatev  2   9   10 , Evgeni Ponimaskin  1 , Josephine Labus  1
Affiliations

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

Kathrin Jahreis et al. Alzheimers Dement. 2023 Dec.

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.

PubMed Disclaimer

References

REFERENCES

    1. Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull. 2016;126:238-292. doi: 10.1016/j.brainresbull.2016.08.018
    1. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:22-35. doi: 10.1038/nrn.2015.1
    1. Pallas-Bazarra N, Jurado-Arjona J, Navarrete M, et al. Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis. EMBO J. 2016;35:1417-1436. doi: 10.15252/embj.201593518
    1. Kandimalla R, Manczak M, Yin X, Wang R, Reddy PH. Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer's disease. Hum Mol Genet. 2018;27:30-40. doi: 10.1093/hmg/ddx381
    1. Paonessa F, Evans LD, Solanki R, et al. Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in Tau-mediated frontotemporal dementia. Cell Rep. 2019;26:582-593.e5. doi: 10.1016/j.celrep.2018.12.085

Publication types