%0 Journal Article
%@ 0036-8075
%A Princen, Katrien
%A Van Dooren, Tom
%A van Gorsel, Marit
%A Louros, Nikolaos
%A Yang, Xiaojuan
%A Dumbacher, Michael
%A Bastiaens, Ilse
%A Coupet, Kristel
%A Dupont, Shana
%A Cuveliers, Eva
%A Lauwers, Annick
%A Laghmouchi, Mohamed
%A Vanwelden, Thomas
%A Carmans, Sofie
%A Van Damme, Nele
%A Duhamel, Hein
%A Vansteenkiste, Seppe
%A Prerad, Jovan
%A Pipeleers, Karolien
%A Rodiers, Olivier
%A De Ridder, Liese
%A Claes, Sofie
%A Busschots, Yoni
%A Pringels, Lentel
%A Verhelst, Vanessa
%A Debroux, Eveline
%A Brouwer, Marinka
%A Lievens, Sam
%A Tavernier, Jan
%A Farinelli, Melissa
%A Hughes-Asceri, Sandrine
%A Voets, Marieke
%A Winderickx, Joris
%A Wera, Stefaan
%A de Wit, Joris
%A Schymkowitz, Joost
%A Rousseau, Frederic
%A Zetterberg, Henrik
%A Cummings, Jeffrey L
%A Annaert, Wim
%A Cornelissen, Tom
%A De Winter, Hans
%A De Witte, Koen
%A Fivaz, Marc
%A Griffioen, Gerard
%D 2024
%F discovery:10193867
%I American Association for the Advancement of Science (AAAS)
%J Science
%K 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
%N 6699
%T Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease
%U https://discovery.ucl.ac.uk/id/eprint/10193867/
%V 384
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.