Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease PMID: 38815015

ADC Targets in Oncology

2026-04-10

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

Science. 2024 May 31;384(6699):eadd6260. doi: 10.1126/science.add6260.

Katrien Princen ^# ¹ , Tom Van Dooren ^# ¹ , Marit van Gorsel ¹ , Nikolaos Louros ² ³ , Xiaojuan Yang ⁴ , Michael Dumbacher ¹ , Ilse Bastiaens ¹ , Kristel Coupet ¹ , Shana Dupont ¹ , Eva Cuveliers ¹ , Annick Lauwers ¹ , Mohamed Laghmouchi ¹ , Thomas Vanwelden ¹ , Sofie Carmans ¹ , Nele Van Damme ¹ , Hein Duhamel ¹ , Seppe Vansteenkiste ¹ , Jovan Prerad ¹ , Karolien Pipeleers ¹ , Olivier Rodiers ¹ , Liese De Ridder ¹ , Sofie Claes ¹ , Yoni Busschots ¹ , Lentel Pringels ¹ , Vanessa Verhelst ¹ , Eveline Debroux ¹ , Marinka Brouwer ⁵ , Sam Lievens ⁶ ⁷ , Jan Tavernier ⁶ ⁷ , Melissa Farinelli ⁸ , Sandrine Hughes-Asceri ⁸ , Marieke Voets ¹ , Joris Winderickx ¹ ⁹ , Stefaan Wera ¹ ¹⁰ , Joris de Wit ⁵ , Joost Schymkowitz ² ³ , Frederic Rousseau ² ³ , Henrik Zetterberg ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶ , Jeffrey L Cummings ¹⁷ , Wim Annaert ⁴ , Tom Cornelissen ¹ , Hans De Winter ¹⁸ , Koen De Witte ¹ , Marc Fivaz ¹ , Gerard Griffioen ¹

Affiliations

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. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
17. 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.
18. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
# Contributed equally.

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.