在阿尔茨海默病模型中，对septins进行药理学调节可恢复钙稳态并具有神经保护作用。
Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.
作者信息
Princen Katrien, Van Dooren Tom, van Gorsel Marit, Louros Nikolaos, Yang Xiaojuan, Dumbacher Michael, Bastiaens Ilse, Coupet Kristel, Dupont Shana, Cuveliers Eva, Lauwers Annick, Laghmouchi Mohamed, Vanwelden Thomas, Carmans Sofie, Van Damme Nele, Duhamel Hein, Vansteenkiste Seppe, Prerad Jovan, Pipeleers Karolien, Rodiers Olivier, De Ridder Liese, Claes Sofie, Busschots Yoni, Pringels Lentel, Verhelst Vanessa, Debroux Eveline, Brouwer Marinka, Lievens Sam, Tavernier Jan, Farinelli Melissa, Hughes-Asceri Sandrine, Voets Marieke, Winderickx Joris, Wera Stefaan, de Wit Joris, Schymkowitz Joost, Rousseau Frederic, Zetterberg Henrik, Cummings Jeffrey L, Annaert Wim, Cornelissen Tom, De Winter Hans, De Witte Koen, Fivaz Marc, Griffioen Gerard
机构信息
reMYND NV, Bio-Incubator, 3001 Leuven-Heverlee, Belgium.
Switch Laboratory, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.
出版信息
Science. 2024 May 31;384(6699):eadd6260. doi: 10.1126/science.add6260.
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.
异常的钙信号传导是阿尔茨海默病（AD）的核心病理组成部分。在此，我们描述了一类名为ReS19-T的化合物的鉴定，它们能够在基于细胞的tau病理模型中恢复钙稳态。异常的tau积累通过重塑细胞皮层的septin细丝导致储存操纵性钙通道（SOCCs）的失控激活。ReS19-T与septins的结合在疾病状态下恢复细丝组装，并抑制通过SOCCs的钙内流。在淀粉样β蛋白和tau驱动的疾病小鼠模型中，ReS19-T药物恢复了突触可塑性，使脑网络活动正常化，并减轻了淀粉样β蛋白和tau病理的发展。我们的研究结果确定septin细胞骨架是开发疾病修饰性AD治疗方法的潜在治疗靶点。
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