Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.
Katrien PrincenTom Van DoorenMarit van GorselNikolaos N LourosXiaojuan YangMichael DumbacherIlse BastiaensKristel CoupetShana DupontEva CuveliersAnnick LauwersMohamed LaghmouchiThomas VanweldenSofie CarmansNele Van DammeHein DuhamelSeppe VansteenkisteJovan PreradKarolien PipeleersOlivier RodiersLiese De RidderSofie ClaesYoni BusschotsLentel PringelsVanessa VerhelstEveline DebrouxMarinka BrouwerSam LievensJan TavernierMelissa FarinelliSandrine Hughes-AsceriMarieke VoetsJoris WinderickxStefaan WeraJoris de WitJoost SchymkowitzFrederic RousseauHenrik ZetterbergJeffrey L CummingsWim AnnaertTom CornelissenHans De WinterKoen De WitteMarc FivazGerard GriffioenPublished in: Science (New York, N.Y.) (2024)
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.