%I American Association for the Advancement of Science (AAAS)
%L discovery10193867
%D 2024
%O This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
%T Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease
%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.
%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
%V 384
%A Katrien Princen
%A Tom Van Dooren
%A Marit van Gorsel
%A Nikolaos Louros
%A Xiaojuan Yang
%A Michael Dumbacher
%A Ilse Bastiaens
%A Kristel Coupet
%A Shana Dupont
%A Eva Cuveliers
%A Annick Lauwers
%A Mohamed Laghmouchi
%A Thomas Vanwelden
%A Sofie Carmans
%A Nele Van Damme
%A Hein Duhamel
%A Seppe Vansteenkiste
%A Jovan Prerad
%A Karolien Pipeleers
%A Olivier Rodiers
%A Liese De Ridder
%A Sofie Claes
%A Yoni Busschots
%A Lentel Pringels
%A Vanessa Verhelst
%A Eveline Debroux
%A Marinka Brouwer
%A Sam Lievens
%A Jan Tavernier
%A Melissa Farinelli
%A Sandrine Hughes-Asceri
%A Marieke Voets
%A Joris Winderickx
%A Stefaan Wera
%A Joris de Wit
%A Joost Schymkowitz
%A Frederic Rousseau
%A Henrik Zetterberg
%A Jeffrey L Cummings
%A Wim Annaert
%A Tom Cornelissen
%A Hans De Winter
%A Koen De Witte
%A Marc Fivaz
%A Gerard Griffioen
%C United States
%J Science
%N 6699