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.
摘要：
钙信号异常是阿尔茨海默病(AD)的重要病理因素。这里,我们描述了一类称为ReS19-T的化合物的鉴定，它们能够在基于细胞的tau病理学模型中恢复钙稳态。异常的tau积累通过重塑细胞皮层的隔膜细丝而导致储存操作的钙通道（SOCC）的不受控制的激活。ReS19-T与隔膜的结合可恢复疾病状态下的细丝组装，并抑制钙通过SOCC进入。在β淀粉样蛋白和tau蛋白驱动的疾病小鼠模型中，ReS19-T药物恢复了突触可塑性，标准化的大脑网络活动，并减弱了淀粉样蛋白β和tau病理的发展。我们的发现将septin细胞骨架确定为疾病改善性AD治疗发展的潜在治疗靶标。
