%0 Journal Article
%T Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.
%A Princen K
%A Van Dooren T
%A van Gorsel M
%A Louros N
%A Yang X
%A Dumbacher M
%A Bastiaens I
%A Coupet K
%A Dupont S
%A Cuveliers E
%A Lauwers A
%A Laghmouchi M
%A Vanwelden T
%A Carmans S
%A Van Damme N
%A Duhamel H
%A Vansteenkiste S
%A Prerad J
%A Pipeleers K
%A Rodiers O
%A De Ridder L
%A Claes S
%A Busschots Y
%A Pringels L
%A Verhelst V
%A Debroux E
%A Brouwer M
%A Lievens S
%A Tavernier J
%A Farinelli M
%A Hughes-Asceri S
%A Voets M
%A Winderickx J
%A Wera S
%A de Wit J
%A Schymkowitz J
%A Rousseau F
%A Zetterberg H
%A Cummings JL
%A Annaert W
%A Cornelissen T
%A De Winter H
%A De Witte K
%A Fivaz M
%A Griffioen G
%J Science
%V 384
%N 6699
%D 2024 May 31
%M 38815015
%F 63.714
%R 10.1126/science.add6260
%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.