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