학술논문
Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.
Document Type
Academic Journal
Author
Princen K; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Van Dooren T; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; van Gorsel M; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Louros N; Switch Laboratory, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.; Yang X; Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research and Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.; Dumbacher M; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Bastiaens I; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Coupet K; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Dupont S; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Cuveliers E; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Lauwers A; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Laghmouchi M; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Vanwelden T; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Carmans S; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Van Damme N; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Duhamel H; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Vansteenkiste S; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Prerad J; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Pipeleers K; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Rodiers O; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; De Ridder L; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Claes S; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Busschots Y; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Pringels L; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Verhelst V; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Debroux E; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Brouwer M; Laboratory of Synapse Biology, VIB Center for Brain & Disease Research and KU Leuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.; Lievens S; Cytokine Receptor Lab, VIB Center for Medical Biotechnology, 9052 Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.; Tavernier J; Cytokine Receptor Lab, VIB Center for Medical Biotechnology, 9052 Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.; Farinelli M; E-PHY-SCIENCE, Bioparc Sophia-Antipolis, 06410 Biot, France.; Hughes-Asceri S; E-PHY-SCIENCE, Bioparc Sophia-Antipolis, 06410 Biot, France.; Voets M; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Winderickx J; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Functional Biology, Department of Biology, KU Leuven, 3001 Leuven-Heverlee, Belgium.; Wera S; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; ViroVet NV, 3001 Leuven-Heverlee, Belgium.; de Wit J; Laboratory of Synapse Biology, VIB Center for Brain & Disease Research and KU Leuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.; Schymkowitz J; Switch Laboratory, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.; Rousseau F; Switch Laboratory, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.; Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; UK Dementia Research Institute at UCL, London WC1E 6BT, UK.; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.; Cummings JL; 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.; Annaert W; Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research and Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.; Cornelissen T; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; De Winter H; Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.; De Witte K; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Fivaz M; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.; Griffioen G; reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
Subject
Language
English
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.