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Science

Publication date: 2024-05-31
Volume: 384
Publisher: American Association for the Advancement of Science

Author:

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

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SYNAPTIC IMPAIRMENT, BETA TOXICITY, TAU, RELEASE, BINDING, MEMORY, ORGANIZATION, POTENTIATION, DISRUPTION, ACTIVATION, Animals, Humans, Mice, Alzheimer Disease, Amyloid beta-Peptides, Calcium, Calcium Channels, Calcium Signaling, Cytoskeleton, Disease Models, Animal, Homeostasis, Neuronal Plasticity, Neuroprotective Agents, Septins, tau Proteins, 12P0919N#54767906, 12P0922N#56382403, C14/21/095#56286976, KA/20/085#56130159, G0I3118N#55623946, G0C4220N#55522043, G0A8320N#55522296, G0A8720N#55522499, 12E0123N#57062350, General Science & Technology

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.