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

• 成果类型: Article
• 署名作者: Princen, Katrien; Van Dooren, Tom; van Gorsel, Marit; Louros, Nikolaos; Yang, Xiaojuan; Dumbacher, Michael; Bastiaens, Ilse; Coupet, Kristel; Dupont, Shana; Cuveliers, Eva; Lauwers, Annick; Laghmouchi, Mohamed; Vanwelden, Thomas; Carmans, Sofie; Van Damme, Nele; Duhamel, Hein; Vansteenkiste, Seppe; Prerad, Jovan; Pipeleers, Karolien; Rodiers, Olivier; De Ridder, Liese; Claes, Sofie; Busschots, Yoni; Pringels, Lentel; Verhelst, Vanessa; Debroux, Eveline; Brouwer, Marinka; Lievens, Sam; Tavernier, Jan; Farinelli, Melissa; Hughes-Asceri, Sandrine; Voets, Marieke; Winderickx, Joris; Wera, Stefaan; de Wit, Joris; Schymkowitz, Joost; Rousseau, Frederic; Zetterberg, Henrik; Cummings, Jeffrey L.; Annaert, Wim; Cornelissen, Tom; De Winter, Hans; De Witte, Koen; Fivaz, Marc; Griffioen, Gerard
• 署名单位: Flanders Institute for Biotechnology (VIB); KU Leuven; Flanders Institute for Biotechnology (VIB); Flanders Institute for Biotechnology (VIB); KU Leuven; Flanders Institute for Biotechnology (VIB); Ghent University; KU Leuven; University of Gothenburg; Sahlgrenska University Hospital; University of London; University College London; University of London; University College London; University of Wisconsin System; University of Wisconsin Madison; Nevada System of Higher Education (NSHE); University of Nevada Las Vegas; University of Antwerp
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9979
• DOI: 10.1126/science.add6260
• 发表日期: 2024-05-31
• 关键词: synaptic impairment; beta toxicity; tau; release; binding; memory; ORGANIZATION; potentiation; disruption; activation

摘要

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-beta and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-beta and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.