Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca²⁺ channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes with age and age-associated diseases. J147 is an Alzheimer’s disease (AD) drug candidate that was identified using a phenotypic screening platform based upon age-related brain toxicities that are mediated by changes in calcium metabolism. The molecular target for J147 is the α-F1-ATP synthase (ATP5A). J147 has therapeutic efficacy in multiple mouse models of AD and accelerated aging and extends life span in flies. A bioinformatics analysis of gene expression in rapidly aging SAMP8 mice during the last quadrant of their life span shows that J147 has a significant effect on ion transport pathways that are changed with aging, making their expression look more like that of younger animals. The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity.

钙失调通常是与衰老和与年龄相关的神经退行性疾病相关的病理学的基础。细胞表达独特的 Ca ^2+模式通道和泵旨在满足特定的生理需求，并且这些过程的保真度随着年龄和与年龄相关的疾病而下降。J147 是一种阿尔茨海默病 (AD) 候选药物，它是使用基于由钙代谢变化介导的与年龄相关的脑毒性的表型筛选平台鉴定的。J147 的分子靶标是 α-F1-ATP 合酶 (ATP5A)。J147 在多种 AD 小鼠模型中具有治疗功效，在果蝇中加速衰老并延长寿命。对快速衰老的 SAMP8 小鼠在其生命最后象限期间的基因表达进行的生物信息学分析表明，J147 对随衰老而改变的离子传输通路具有显着影响，使它们的表达看起来更像年轻动物。然后在细胞培养神经毒性测定中研究了这些变化的分子基础，这是 J147 开发的主要筛选。在这里，我们显示 J147 及其分子靶标 ATP 合酶在急性神经毒性期间调节钙池操纵钙进入 (SOCE) 和细胞死亡的维持。