Article
作者: Annaert, Wim ; Yang, Xiaojuan ; De Witte, Koen ; Duhamel, Hein ; Vanwelden, Thomas ; Dupont, Shana ; Louros, Nikolaos ; Cornelissen, Tom ; Busschots, Yoni ; Wera, Stefaan ; Princen, Katrien ; Bastiaens, Ilse ; Claes, Sofie ; van Gorsel, Marit ; Vansteenkiste, Seppe ; Schymkowitz, Joost ; Rousseau, Frederic ; De Winter, Hans ; Cuveliers, Eva ; Prerad, Jovan ; Lauwers, Annick ; de Wit, Joris ; Coupet, Kristel ; Laghmouchi, Mohamed ; Zetterberg, Henrik ; Dumbacher, Michael ; Cummings, Jeffrey L ; Van Dooren, Tom ; Verhelst, Vanessa ; Pipeleers, Karolien ; Rodiers, Olivier ; Debroux, Eveline ; Winderickx, Joris ; Farinelli, Melissa ; Tavernier, Jan ; De Ridder, Liese ; Hughes-Asceri, Sandrine ; Brouwer, Marinka ; Griffioen, Gerard ; Van Damme, Nele ; Voets, Marieke ; Fivaz, Marc ; Lievens, Sam ; Carmans, Sofie ; Pringels, Lentel
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.