Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease-Reference-Cited by-同舟云学术

Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease

Published:2024-05-31 Issue:6699 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Princen Katrien¹^ORCID,Van Dooren Tom¹^ORCID,van Gorsel Marit¹^ORCID,Louros Nikolaos²³^ORCID,Yang Xiaojuan⁴^ORCID,Dumbacher Michael¹,Bastiaens Ilse¹,Coupet Kristel¹,Dupont Shana¹,Cuveliers Eva¹^ORCID,Lauwers Annick¹^ORCID,Laghmouchi Mohamed¹,Vanwelden Thomas¹,Carmans Sofie¹,Van Damme Nele¹^ORCID,Duhamel Hein¹^ORCID,Vansteenkiste Seppe¹,Prerad Jovan¹,Pipeleers Karolien¹,Rodiers Olivier¹,De Ridder Liese¹,Claes Sofie¹,Busschots Yoni¹,Pringels Lentel¹,Verhelst Vanessa¹^ORCID,Debroux Eveline¹^ORCID,Brouwer Marinka⁵,Lievens Sam⁶⁷,Tavernier Jan⁶⁷,Farinelli Melissa⁸^ORCID,Hughes-Asceri Sandrine⁸^ORCID,Voets Marieke¹^ORCID,Winderickx Joris¹⁹^ORCID,Wera Stefaan¹¹⁰,de Wit Joris⁵^ORCID,Schymkowitz Joost²³^ORCID,Rousseau Frederic²³^ORCID,Zetterberg Henrik¹¹¹²¹³¹⁴¹⁵^ORCID,Cummings Jeffrey L.¹⁶^ORCID,Annaert Wim⁴^ORCID,Cornelissen Tom¹^ORCID,De Winter Hans¹⁷^ORCID,De Witte Koen¹,Fivaz Marc¹^ORCID,Griffioen Gerard¹^ORCID

Affiliation:

1. reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.

2. Switch Laboratory, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.

3. Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.

4. Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research and Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.

5. Laboratory of Synapse Biology, VIB Center for Brain & Disease Research and KU Leuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.

6. Cytokine Receptor Lab, VIB Center for Medical Biotechnology, 9052 Ghent, Belgium.

7. Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.

8. E-PHY-SCIENCE, Bioparc Sophia-Antipolis, 06410 Biot, France.

9. Functional Biology, Department of Biology, KU Leuven, 3001 Leuven-Heverlee, Belgium.

10. ViroVet NV, 3001 Leuven-Heverlee, Belgium.

11. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden.

12. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden.

13. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.

14. UK Dementia Research Institute at UCL, London WC1E 6BT, UK.

15. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.

16. Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas, NV 89154, USA.

17. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.

Abstract

Abnormal calcium signaling is a central pathological component of Alzheimer’s disease (AD). Here, we describe the identification of a class of compounds called ReS19-T, which are able to restore calcium homeostasis in cell-based models of tau pathology. Aberrant tau accumulation leads to uncontrolled activation of store-operated calcium channels (SOCCs) by remodeling septin filaments at the cell cortex. Binding of ReS19-T to septins restores filament assembly in the disease state and restrains calcium entry through SOCCs. In amyloid-β and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-β and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.add6260

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