Amongst the cellular cacophony of altered signals in Alzheimer’s disease (AD), disrupted Ca²⁺ homeostasis and consequential endoplasmic reticulum (ER) stress signals have been recognized as key determinants of neuron fate. This altered Ca²⁺ state is accompanied by a failing sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, which has been recognized as a causal feature of the underlying disease state. Repair of the Ca²⁺ dyshomeostasis represents a putative drug target via alleviation of ER stress and rescue of injured neurons, effectively modifying the AD state. Herein, we report a small molecule SERCA activator that rescues brain cells and raises ER Ca²⁺ in vitro, and shows efficacy in the APP/PS1 double transgenic mouse model of Alzheimer’s disease. These results support SERCA activation as a therapeutic target for AD.

在阿尔茨海默氏病（AD）中信号改变的细胞杂音中，Ca ²⁺稳态失调和相应的内质网（ER）应激信号已被认为是神经元命运的关键决定因素。这种改变的Ca ²⁺状态伴随着衰竭的肌膜/内质网Ca ²⁺ -ATPase（SERCA）泵，这已被认为是潜在疾病状态的因果特征。Ca ²⁺运动异常的修复代表通过缓解ER应激和挽救受损神经元，有效改变AD状态的推定药物靶标。在此，我们报道了一种小分子SERCA激活剂，它可以拯救脑细胞并提高ER Ca ²⁺并在APP / PS1双转基因阿尔茨海默氏病小鼠模型中显示功效。这些结果支持SERCA激活作为AD的治疗靶标。